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Now in its 25th year, the Mutant Mouse Resource and Research Center (MMRRC) consortium continues to serve the United States and international biomedical scientific community as a public repository and distribution archive of laboratory mouse models of human disease for research. Supported by the National Institutes of Health (NIH), the MMRRC consists of 4 regionally distributed and dedicated vivaria, offices, and specialized laboratory facilities and an Informatics Coordination and Service Center (ICSC). The overarching purpose of the MMRRC is to facilitate groundbreaking biomedical research by offering an extensive repertoire of mutant mice that are essential for advancing the understanding of human physiology and disease. The function of the MMRRC is to identify, acquire, evaluate, characterize, cryopreserve, and distribute mutant mouse strains to qualified biomedical investigators around the nation and the globe. Mouse strains accepted from the research community are held to the highest scientific standards to optimize reproducibility and enhance scientific rigor and transparency. All submitted strains are thoroughly reviewed, documented, and validated using extensive scientific quality control measures. In addition, the MMRRC conducts resource-related research on cryopreservation, mouse genetics, environmental conditions, and other topics that enhance operations of the MMRRC. Today, the MMRRC maintains an archive of mice, cryopreserved embryos and sperm, embryonic stem (ES) cell lines, and murine hybridomas for nearly 65,000 alleles. Since its inception, the MMRRC has fulfilled more than 20,000 orders from 13,651 scientists at 8441 institutions worldwide. The MMRRC also provides numerous services to assist researchers, including scientific consultation, technical assistance, genetic assays, microbiome analysis, analytical phenotyping, pathology, cryorecovery, husbandry, breeding and colony management, infectious disease surveillance, and disease modeling. The ICSC coordinates MMRRC operations, interacts with researchers, and manages the website (mmrrc.org) and online catalogue. Researchers benefit from an expansive list of well-defined mouse models of disease that meet the highest scientific standards while submitting investigators benefit by having their mouse strains cryopreserved, protected, and distributed in compliance with NIH policies. [ABSTRACT FROM AUTHOR]

Deleterious accumulation of R-loops, a DNA-RNA hybrid structure, contributes to genome instability. They are associated with BRCA1 mutation-related breast cancer, an estrogen receptor α negative (ERα-) tumor type originating from luminal progenitor cells. However, a presumed causality of R-loops in tumorigenesis has not been established in vivo. Here, we overexpress mouse Rnaseh1 (Rh1-OE) in vivo to remove accumulated R-loops in Brca1-deficient mouse mammary epithelium (BKO). R-loop removal exacerbates DNA replication stress in proliferating BKO mammary epithelial cells, with little effect on homology-directed repair of double-strand breaks following ionizing radiation. Compared to their BKO counterparts, BKO-Rh1-OE mammary glands contain fewer luminal progenitor cells but more mature luminal cells. Despite a similar incidence of spontaneous mammary tumors in BKO and BKO-Rh1-OE mice, a significant percentage of BKO-Rh1-OE tumors express ERα and progesterone receptor. Our results suggest that rather than directly elevating the overall tumor incidence, R-loops influence the mammary tumor subtype by shaping the cell of origin for Brca1 tumors. [ABSTRACT FROM AUTHOR]

GABAergic neurons represent 10–15% of the neuronal population of the cortex but exert a powerful control over information flow in cortical circuits. The largest GABAergic class in the neocortex is represented by the parvalbumin‐expressing fast‐spiking neurons, which provide powerful somatic inhibition to their postsynaptic targets. Recently, the density of parvalbumin interneurons has been shown to be lower in associative areas of the mouse cortex as compared with sensory and motor areas. Modelling work based on these quantifications linked the low‐density of parvalbumin interneurons with specific computations of associative cortices. However, it is still unknown whether the total GABAergic population of association cortices is smaller or whether another GABAergic type can compensate for the low density of parvalbumin interneurons. In the present study, we investigated these hypotheses using a combination of neuroanatomy, mouse genetics and neurophysiology. We found that the GABAergic population of association areas is comparable with that of primary sensory areas, and it is enriched of fast‐spiking neurons that do not express parvalbumin and were not accounted for by previous quantifications. We developed an intersectional viral strategy to demonstrate that the population of fast‐spiking neurons is comparable across cortical regions. Our results provide quantifications of the density of fast‐spiking GABAergic neurons and offers new biological constrains to refine current models of cortical computations. [ABSTRACT FROM AUTHOR]

Greg Lemke's laboratory was one of the pioneers of research into the TAM family of receptor tyrosine kinases (RTKs). Not only was Tyro3 cloned in his laboratory, but his group also extensively studied mice knocked out for individual or various combinations of the TAM RTKs Tyro3, Axl, and Mertk. Here we primarily focus on one of the paralogs—MERTK. We provide a historical perspective on rodent models of loss of Mertk function and their association with retinal degeneration and blindness. We describe later studies employing mouse genetics and the generation of newer knockout models that point out incongruencies with the inference that loss of MERTK-dependent phagocytosis is sufficient for severe, early-onset photoreceptor degeneration in mice. This discussion is meant to raise awareness with regards to the limitations of the original Mertk knockout mouse model generated using 129 derived embryonic stem cells and carrying 129 derived alleles and the role of these alleles in modifying Mertk knockout phenotypes or even displaying Mertk-independent phenotypes. We also suggest molecular approaches that can further Greg Lemke's scintillating legacy of dissecting the molecular functions of MERTK—a protein that has been described to function in phagocytosis as well as in the negative regulation of inflammation. [ABSTRACT FROM AUTHOR]

In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Reexpression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis. [ABSTRACT FROM AUTHOR]

Cell segregation allows the compartmentalization of cells with similar fates during morphogenesis, which can be enhanced by cell fate plasticity in response to local molecular and biomechanical cues. Endothelial tip cells in the growing retina, which lead vessel sprouts, give rise to arterial endothelial cells and thereby mediate arterial growth. Here, we have combined cell type-specific and inducible mouse genetics, flow experiments in vitro, single-cell RNA sequencing and biochemistry to show that the balance between ephrin-B2 and its receptor EphB4 is critical for arterial specification, cell sorting and arteriovenous patterning. At the molecular level, elevated ephrin-B2 function after loss of EphB4 enhances signaling responses by the Notch pathway, VEGF and the transcription factor Dach1, which is influenced by endothelial shear stress. Our findings reveal how Eph-ephrin interactions integrate cell segregation and arteriovenous specification in the vasculature, which has potential relevance for human vascular malformations caused by EPHB4 mutations. Arteries are vital blood vessels for our body and their growth and patterning are critical for proper blood flow. Here they use a retina model to show that a balance of EphB4 receptor and ephrin-B2 ligand integrate a well-wired molecular network to control arteriovenous patterning and vascular growth. [ABSTRACT FROM AUTHOR]

Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like protein covalently conjugated with intracellular proteins through UFMylation, a process similar to ubiquitylation. Growing lines of evidence regarding not only the structural basis of the components essential for UFMylation but also their biological properties shed light on crucial roles of the UFM1 system in the endoplasmic reticulum (ER), such as ER-phagy and ribosome-associated quality control at the ER, although there are some functions unrelated to the ER. Mouse genetics studies also revealed the indispensable roles of this system in hematopoiesis, liver development, neurogenesis, and chondrogenesis. Of critical importance, mutations of genes encoding core components of the UFM1 system in humans cause hereditary developmental epileptic encephalopathy and Schohat-type osteochondrodysplasia of the epiphysis. Here, we provide a multidisciplinary review of our current understanding of the mechanisms and cellular functions of the UFM1 system as well as its pathophysiological roles, and discuss issues that require resolution. A growing body of evidence is accumulating to show the importance of the UFM1 system in the endoplasmic reticulum (ER), such as ER-phagy and ER-RQC. In this review, we will introduce the mechanisms and cellular functions of the UFM1 system in the ER as well as its pathophysiological roles. [ABSTRACT FROM AUTHOR]

Neural computations arise from highly precise connections between specific types of neurons. Retinal ganglion cells (RGCs) with similar stratification patterns are positioned to receive similar inputs but often display different response properties. In this study, we used intersectional mouse genetics to achieve single-cell type labeling and identified an object motion sensitive (OMS) AC type, COMS-AC(counter-OMS AC). Optogenetic stimulation revealed that COMS-AC makes glycinergic synapses with the OMS-insensitive HD2p-RGC, while chemogenetic inactivation showed that COMS-AC provides inhibitory control to HD2p-RGC during local motion. This local inhibition, combined with the inhibitory drive from TH2-AC during global motion, explains the OMS-insensitive feature of HD2p-RGC. In contrast, COMS-AC fails to make synapses with W3(UHD)-RGC, allowing it to exhibit OMS under the control of VGlut3-AC and TH2-AC. These findings reveal modular interneuron circuits that endow structurally similar RGC types with different responses and present a mechanism for redundancy-reduction in the retina to expand coding capacity. Interneuron circuits in the retina allow structurally similar retinal ganglion cells to show different responses. Here the authors use an intersectional genetics approach to identify an object motion sensitive amacrine cell subtype in the mouse retina. [ABSTRACT FROM AUTHOR]

The molecular etiology of idiopathic pulmonary fibrosis (IPF) has been extensively investigated to identify new therapeutic targets. Although anti-inflammatory treatments are not effective for patients with IPF, damaged alveolar epithelial cells play a critical role in lung fibrogenesis. Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells. Using this in vitro model and mouse genetics, we demonstrate that bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation. Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis. These findings provide insights into the mechanism of IPF and potential therapeutic targets. IPF is a progressive disease with few inflammatory pathology. Here, using alveolar organoid technology, the authors identified autocrine TGF-β-positive feedback in AT2-lineage cells as a core mechanism of inflammation-independent lung fibrogenesis. [ABSTRACT FROM AUTHOR]

The limited information about how descending inputs from the brain and sensory inputs from the periphery use spinal cord interneurons (INs) is a major barrier to understanding how these inputs may contribute to motor functions under normal and pathologic conditions. Commissural interneurons (CINs) are a heterogeneous population of spinal INs that has been implicated in crossed motor responses and bilateral motor coordination (ability to use the right and left side of the body in a coordinated manner) and, therefore, are likely involved in many types of movement (e.g., dynamic posture stabilization, jumping, kicking, walking). In this study, we incorporate mouse genetics, anatomy, electrophysiology, and single-cell calcium imaging to investigate how a subset of CINs, those with descending axons called dCINs, are recruited by descending reticulospinal and segmental sensory signals independently and in combination. We focus on two groups of dCINs set apart by their principal neurotransmitter (glutamate and GABA) and identified as VGluT2+ dCINs and GAD2+ dCINs. We show that VGluT2+ and GAD2+ dCINs are both extensively recruited by reticulospinal and sensory input alone but that VGluT2+ and GAD2+ dCINs integrate these inputs differently. Critically, we find that when recruitment depends on the combined action of reticulospinal and sensory inputs (subthreshold inputs), VGluT2+ dCINs, but not GAD2+ dCINs, are recruited. This difference in the integrative capacity of VGluT2+ and GAD2+ dCINs represents a circuit mechanism that the reticulospinal and segmental sensory systems may avail themselves of to regulate motor behaviors both normally and after injury. [ABSTRACT FROM AUTHOR]

Cryopreservation, or the freezing of embryos or sperm, has become a routine part of many research projects involving laboratory mice. In this article, we combine historical and sociological methods to produce a cryopolitical analysis of this less explored aspect of animal research. We provide a longitudinal account of mouse embryo and semen storage and uses in the UK and show that cryopreservation enabled researchers to overcome particular challenges—fears of strain loss, societal disapproval, and genetic drift—in ways which enabled the continued existence of strains and contributed to the scaling up of mouse research since World War II. We use the theoretical lens of cryopolitics to explore three different, yet overlapping, cryopolitical strategies that we identify. All share the ability to ensure the continued maintenance of genetically defined strains without the need for continually breeding colonies of mice. We argue that, in contrast to more common imaginaries of species conservation, the cryopolitical rationale can best be understood as purposefully not letting the strain die without requiring animals to live. The ability to freeze mice, then, had the potential to unsettle who the objects of care are in mouse research, from individual animals to the concept of the strain itself. [ABSTRACT FROM AUTHOR]

The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are critically important hubs in the endogenous analgesia pathway. Technological and conceptual advances have permitted the identification and targeting of neural ensembles in the PAG and RVM during complex behaviors, revealing that they divergently modulate distinct components of somatosensation. In vivo imaging, viral tracing, and molecular genetic manipulations have afforded a new layer of insight by characterizing the function of genetically defined neuronal populations within the PAG and RVM. How these identified pathways coordinate other autonomic, motivational, and defensive responses during ongoing nociception remains to be addressed in greater detail. Further investigations into the PAG and RVM in the descending modulation of nociception, itch, and other complex behaviors are ongoing. Decades of research have suggested that stimulation of supraspinal structures, such as the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), inhibits nocifensive responses to noxious stimulation through a process known as descending modulation. Electrical stimulation and pharmacologic manipulations of the PAG and RVM identified transmitters and neuronal firing patterns that represented distinct cell types. Advances in mouse genetics, in vivo imaging, and circuit tracing methods, in addition to chemogenetic and optogenetic approaches, allowed the characterization of the cells and circuits involved in descending modulation in further detail. Recent work has revealed the importance of PAG and RVM neuronal cell types in the descending modulation of pruriceptive as well as nociceptive behaviors, underscoring their roles in coordinating complex behavioral responses to sensory input. This review summarizes how new technical advances that enable cell type-specific manipulation and recording of neuronal activity have supported, as well as expanded, long-standing views on descending modulation. [ABSTRACT FROM AUTHOR]

Among asthmatics, there is significant heterogeneity in the clinical presentation and underlying pathophysiological mechanisms, leading to the recognition of multiple disease endotypes (e.g., T2-high vs. T2-low). This heterogeneity extends to severe asthmatics, who may struggle to control symptoms even with high-dose corticosteroid treatment and other therapies. However, there are limited mouse models available to model the spectrum of severe asthma endotypes. We sought to identify a new mouse model of severe asthma by first examining responses to chronic allergen exposure among strains from the Collaborative Cross (CC) mouse genetics reference population, which contains greater genetic diversity than other inbred strain panels previously used for models of asthma. Mice from five CC strains and the often-used classical inbred strain BALB/cJ were chronically exposed to house dust mite (HDM) allergen for five weeks followed by measurements of airway inflammation. CC strain CC011/UncJ (CC011) exhibited extreme responses to HDM including high levels of airway eosinophilia, elevated lung resistance, and extensive airway wall remodeling, and even fatalities among ~ 50% of mice prior to study completion. Compared to BALB/cJ mice, CC011 mice had stronger Th2-mediated airway responses demonstrated by significantly elevated total and HDM-specific IgE and increased Th2 cytokines during tests of antigen recall, but not enhanced ILC2 activation. Airway eosinophilia in CC011 mice was completely dependent upon CD4+ T-cells. Notably, we also found that airway eosinophilia in CC011 mice was resistant to dexamethasone steroid treatment. Thus, the CC011 strain provides a new mouse model of T2-high, severe asthma driven by natural genetic variation likely acting through CD4+ T-cells. Future studies aimed at determining the genetic basis of this phenotype will provide new insights into mechanisms underlying severe asthma. [ABSTRACT FROM AUTHOR]

The Cre-lox system is a versatile and powerful tool used in mouse genetics. It allows spatial and/or temporal control of the deletion of a target gene. The Rosa26-CreERT2 (R26CreERT2) mouse model allows ubiquitous expression of CreERT2. Once activated by tamoxifen, CreERT2 will enter into the nuclei and delete floxed DNA sequences. Here, we show that intraperitoneal injection of tamoxifen in young R26CreERT2 mice leads to morbidity and mortality within 10 days after the first injection, in the absence of a floxed allele. Activation of CreERT2 by tamoxifen led to severe hematological defects, with anemia and a strong disorganization of the bone marrow vascular bed. Cell proliferation was significantly reduced in the bone marrow and the spleen resulting in the depletion of several hematopoietic cells. However, not all cell types or organs were affected to the same extent. We realized that many research groups are not aware of the potential toxicity of Cre recombinases, resulting in misinterpretation of the observed phenotype and in a waste of time and resources. We discuss the necessity to include tamoxifen injected CreERT2 controls lacking a floxed allele in experimental designs and to improve communication about the limitations of Cre-lox mouse models among the scientific community. [ABSTRACT FROM AUTHOR]

Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies. [ABSTRACT FROM AUTHOR]

Grasshopper mice of the genus Onychomys , represented by three living species in North America, have a long and controversial taxonomic history. Usually allocated to either the cricetine or neotomine cricetids, they also have been considered to represent a distinct tribe. Since the discovery and description of the extinct grasshopper mouse relative Acrolophomys rhodopetros from the late Miocene of the upper Dove Spring Formation of California, dated at 9.3–8.8 Ma, it has become apparent that the grasshopper mouse clade has a long, distinct evolutionary history. Using a combination of morphological (including paleontological material) and molecular data, we reassessed the phylogenetic position of grasshopper mice. A morphological phylogenetic analysis was done on fossil and modern specimens of all recognized neotomine tribes, including craniodental, phallic, and soft tissue characters. A DNA-based matrix was constructed including 72 species representing all known living genera of Neotominae and 13 outgroup taxa belonging mostly to cricetid subfamilies. DNA sampling covered the mitochondrial protein-coding gene cytochrome-b (Cytb), and seven nuclear loci. The morphological analysis yielded a single most parsimonious tree of 42 steps, placing Ochrotomys (Ochrotomyini), Baiomys (Baiomyini), Reithrodontomys (Reithrodontomyini), and an Onychomys–Acrolophomys clade as successive sister clades to a Peromyscus clade, respectively. The molecular phylogenetic analyses recovered seven major clades: (1) a clade including Habromys , Megadontomys , Neotomodon, Osgoodomys, Podomys , and a paraphyletic Peromyscus clade, sister to (2) a second clade containing extant Onychomys species, (3) a Reithrodontomys clade, (4) an Isthmomys clade, (5) a clade including Baiomys and Scotinomys , (6) an Ochrotomys clade, and (7) a well--supported clade containing Hodomys , Neotoma , and Xenomys. A Bayesian combined morphological and molecular analysis recovered the same major phylogenetic associations as the molecular analyses. The sum of molecular markers and morphological traits expressed by Acrolophomys and Onychomys leads to a phylogenetic position supporting their recognition as a distinct tribe. [ABSTRACT FROM AUTHOR]

Obesity plays an important role in the development of insulin resistance and diabetes, but the molecular mechanism that links obesity and diabetes is still not completely understood. Here, we used 146 targeted metabolomic profiles from the German KORA FF4 cohort consisting of 1715 participants and associated them with obesity and type 2 diabetes. In the basic model, 83 and 51 metabolites were significantly associated with body mass index (BMI) and T2D, respectively. Those metabolites are branched-chain amino acids, acylcarnitines, lysophospholipids, or phosphatidylcholines. In the full model, 42 and 3 metabolites were significantly associated with BMI and T2D, respectively, and replicate findings in the previous studies. Sobel mediation testing suggests that the effect of BMI on T2D might be mediated via lipids such as sphingomyelin (SM) C16:1, SM C18:1 and diacylphosphatidylcholine (PC aa) C38:3. Moreover, mendelian randomization suggests a causal relationship that BMI causes the change of SM C16:1 and PC aa C38:3, and the change of SM C16:1, SM C18:1, and PC aa C38:3 contribute to T2D incident. Biological pathway analysis in combination with genetics and mice experiments indicate that downregulation of sphingolipid or upregulation of phosphatidylcholine metabolism is a causal factor in early-stage T2D pathophysiology. Our findings indicate that metabolites like SM C16:1, SM C18:1, and PC aa C38:3 mediate the effect of BMI on T2D and elucidate their role in obesity related T2D pathologies. [ABSTRACT FROM AUTHOR]

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in vivo evidence that regional identity in the embryonic cochlea acts as a framework upon which tonotopy-specific properties essential for frequency selectivity in the mature cochlea develop. We found that follistatin (FST) is required for the maintenance of apical cochlear identity, but dispensable for its initial induction. In a fate-mapping analysis, we found that FST promotes expansion of apical cochlear cells, contributing to the formation of the apical cochlear domain. SHH, in contrast, is required both for the induction and maintenance of apical identity. In the absence of FST or SHH, mice produce a short cochlea lacking its apical domain. This results in the loss of apex-specific anatomical and molecular properties and low-frequency-specific hearing loss. [ABSTRACT FROM AUTHOR]

The T/t complex of the mouse attracted many of the major figures of mouse genetics to perform genetic, cytogenetic, physiological, biochemical and molecular biological studies of it. These studies started with the discovery of short tailed mutants (Ts) and recessive lethal developmental mutations (ts) which mapped to the same “locus” in the early 1920s in France. However, due to the non-receptivity of French scientists to genetics, they continued to be studied in mostly Anglophone countries to be joined by a wider international community in the 1970s. These discoveries led to developmental studies of the lethal mutants which provided the origin of mammalian developmental genetics. The fascinating property of transmission ratio distortion (non-50/50 segregation of alleles in offspring of males) elicited tremendous interest. There were false leads (that the region consisted of unusual DNA, that the alleles controlled cell surface antigens on embryonic cells and spermatozoa) and exciting discoveries. This historical review provides a review of this extensive area of research and some of the individuals involved in it. [ABSTRACT FROM AUTHOR]

Inbred mouse strains have long proved useful as tools for biomedical research. They remove the effects of genetic background as an experimental variable. Within all mouse colonies, genetic drift is a recognised phenomenon and monitoring and documenting changes is important for experimental design and consistency. This communication documents the initial characterisation through SNP analysis of the inbred mouse strains bred and used at the time at the Medical Research Council National Institute for Medical Research (MRC-NIMR), Mill Hill, now The Crick Institute. These inbred strains were part of the foundation colonies for the many genetically modified mouse strains made at Mill Hill. We found small genetic changes in four of the nine inbred strains. Although phenotypic differences have not yet been found between the NIMR and the correspondent parental strains, I cannot discard that these may arise or have already arisen. This work has also authenticated the 129/SvJEvNimr-Gpi1c strain that was widely used at MRC-NIMR for gene targeting. All these inbred strains have been renamed according to The International Committee on Standardized Genetic Nomenclature for Mice. [ABSTRACT FROM AUTHOR]

Robust locomotion relies on information from proprioceptors: sensory organs that communicate the position of body parts to the spinal cord and brain. Proprioceptive circuits in the spinal cord are known to coarsely regulate locomotion in the presence of perturbations. Yet, the regulatory importance of the brain in maintaining robust locomotion remains less clear. Here, through mouse genetic studies and in vivo electrophysiology, we examined the role of the brain in integrating proprioceptive information during perturbed locomotion. The systemic removal of proprioceptors left the mice in a constantly perturbed state, similar to that observed during mechanically perturbed locomotion in wild‐type mice and characterised by longer and less accurate synergistic activation patterns. By contrast, after surgically interrupting the ascending proprioceptive projection to the brain through the dorsal column of the spinal cord, wild‐type mice showed normal walking behaviour, yet lost the ability to respond to external perturbations. Our findings provide direct evidence of a pivotal role for ascending proprioceptive information in achieving robust, safe locomotion. Key points: Whether brain integration of proprioceptive feedback is crucial for coping with perturbed locomotion is not clear.We showed a crucial role of the brain for responding to external perturbations and ensure robust locomotion.We used mouse genetics to remove proprioceptors and a spinal lesion model to interrupt the flow of proprioceptive information to the brain through the dorsal column in wild‐type animals.Using a custom‐built treadmill, we administered sudden and random mechanical perturbations to mice during walking.External perturbations affected locomotion in wild‐type mice similar to the absence of proprioceptors in genetically modified mice.Proprioceptive feedback from muscle spindles and Golgi tendon organs contributed to locomotor robustness.Wild‐type mice lost the ability to respond to external perturbations after interruption of the ascending proprioceptive projection to the brainstem. [ABSTRACT FROM AUTHOR]

Abstract: Migraine is a complex neurovascular disorder that is one of the leading causes of disability and a reduced quality of life. Even with such a high societal impact, our understanding of the cellular and molecular mechanisms that contribute to migraine headaches is limited. To address this complex disorder, several groups have performed genome-wide association studies to elucidate migraine susceptibility genes, with many identifying transient receptor potential melastatin 8 (TRPM8), a cold-sensitive cation channel expressed in peripheral afferents innervating the trigeminovascular system, and the principal mediator of cold and cold pain associated with injury and disease. Interestingly, these migraine-associated single-nucleotide polymorphisms reside in noncoding regions of TRPM8, with those correlated with reduced migraine risk exhibiting lower TRPM8 expression and decreased cold sensitivity. Nonetheless, as a role for TRPM8 in migraine has yet to be defined, we sought to address this gap in our knowledge using mouse genetics and TRPM8 antagonism to determine whether TRPM8 channels or neurons are required for migraine-like pain (mechanical allodynia and facial grimace) in inducible migraine models. Our results show that both evoked and spontaneous pain behaviors are dependent on both TRPM8 channels and neurons, as well as required in both acute and chronic migraine models. Moreover, inhibition of TRPM8 channels prevented acute but not established chronic migraine-like pain. These results are consistent with its association with migraine in genetic analyses and establish that TRPM8 channels are a component of the underlying mechanisms of migraine. [ABSTRACT FROM AUTHOR]

Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2–4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma. Rare variant association data from human genetics combined with in vitro and in vivo functional validation highlight ANGPTL7 as a promising therapeutic target for intraocular pressure reduction, and protection from glaucoma. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), where amyloid-β (Aβ) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aβ- and tau-driven AD mouse models. To this end, our work defines the first specific function of LAMP5 interneurons in neuronal network hyperexcitation in AD and dementia with tau pathology. [ABSTRACT FROM AUTHOR]

Background: The turtle carapace is an evolutionary novelty resulting from changes in the processes that build ribs and their associated muscles in most tetrapod species. Turtle embryos have several unique features that might play a role in this process, including the carapacial ridge, a Myf5 gene with shorter coding region that generates an alternative splice variant lacking exon 2, and unusual expression patterns of Lbx1 and HGF. Results: We investigated these turtle‐specific expression differences using genetic approaches in mouse embryos. At mid‐gestation, mouse embryos producing Myf5 transcripts lacking exon 2 replicated some early properties of turtle somites, but still developed into viable and fertile mice. Extending Lbx1 expression into the hypaxial dermomyotomal lip of trunk somites to mimic the turtle Lbx1 expression pattern, produced fusions in the distal part of the ribs. Conclusions: Turtle‐like Myf5 activity might generate a plastic state in developing trunk somites under which they can either enter carapace morphogenetic routes, possibly triggered by signals from the carapacial ridge, or still engage in the development of a standard tetrapod ribcage in the absence of those signals. In addition, trunk Lbx1 expression might play a later role in the formation of the lateral border of the carapace. Key Findings: Mouse embryos expressing turtle‐like Myf5 lacking exon2 display alterations in trunk somites resembling features observed in turtle embryosTurtle‐type Myf5 expression is not sufficient to produce mature carapace‐like structuresActivation of Lbx1 in trunk somites produce distal rib fusions [ABSTRACT FROM AUTHOR]

The International Mouse Phenotyping Consortium (IMPC) is a worldwide effort producing and phenotyping knockout mouse lines to expose the pathophysiological roles of all genes in human diseases and make mice and data available and accessible to the global research community. It has created new knowledge on the function of thousands of genes for which little to anything was known. This new knowledge has informed the genetic basis of rare diseases, posited gene product influences on common diseases, influenced research on targeted therapies, revealed functional pleiotropy, essentiality, and sexual dimorphism, and many more insights into the role of genes in health and disease. Its scientific contributions have been many and widespread, however there remain thousands of "dark" genes yet to be illuminated. Nearing the end of its current funding cycle, IMPC is at a crossroads. The vision forward is clear, the path to proceed less so., (© 2024. The Author(s).)

We recently reported that a neurosteroid analogue with T-channel-blocking properties (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH), induced hypnosis in rat pups without triggering neuronal apoptosis. Furthermore, we found that the inhibition of the CaV3.1 isoform of T-channels contributes to the hypnotic properties of 3β-OH in adult mice. However, the specific mechanisms underlying the role of other subtypes of voltage-gated calcium channels in thalamocortical excitability and oscillations in vivo during 3β-OH-induced hypnosis are largely unknown. Here, we used patch-clamp recordings from acute brain slices, in vivo electroencephalogram (EEG) recordings, and mouse genetics with wild-type (WT) and CaV2.3 knock-out (KO) mice to further investigate the molecular mechanisms of neurosteroid-induced hypnosis. Our voltage-clamp recordings showed that 3β-OH inhibited recombinant CaV2.3 currents. In subsequent current-clamp recordings in thalamic slices ex vivo , we found that selective CaV2.3 channel blocker (SNX-482) inhibited stimulated tonic firing and increased the threshold for rebound burst firing in WT animals. Additionally, in thalamic slices we found that 3β-OH inhibited spike-firing more profoundly in WT than in mutant mice. Furthermore, 3β-OH reduced bursting frequencies in WT but not mutant animals. In ensuing in vivo experiments, we found that intra-peritoneal injections of 3β-OH were less effective in inducing LORR in the mutant mice than in the WT mice, with expected sex differences. Furthermore, the reduction in total α, β, and low γ EEG power was more profound in WT than in CaV2.3 KO females over time, while at 60 min after injections of 3β-OH, the increase in relative β power was higher in mutant females. In addition, 3β-OH depressed EEG power more strongly in the male WT than in the mutant mice and significantly increased the relative δ power oscillations in WT male mice in comparison to the mutant male animals. Our results demonstrate for the first time the importance of the CaV2.3 subtype of voltage-gated calcium channels in thalamocortical excitability and the oscillations that underlie neurosteroid-induced hypnosis. [ABSTRACT FROM AUTHOR]

CaV2.3 channels are subthreshold voltage-gated calcium channels that play crucial roles in neurotransmitter release and regulation of membrane excitability, yet modulation of these channels with endogenous molecules and their role in pain processing is not well studied. Here, we hypothesized that an endogenous amino acid l-cysteine could be a modulator of these channels and may affect pain processing in mice. To test this hypothesis, we employed conventional patch-clamp technique in the whole-cell configuration using recombinant CaV2.3 subunit stably expressed in human embryonic kidney (HEK-293) cells. We found in our in vitro experiments that l-cysteine facilitated gating and increased the amplitudes of recombinant CaV2.3 currents likely by chelating trace metals that tonically inhibit the channel. In addition, we took advantage of mouse genetics in vivo using the acetic acid visceral pain model that was performed on wildtype and homozygous Cacna1e knockout male littermates. In ensuing in vivo experiments, we found that l-cysteine administered both subcutaneously and intraperitoneally evoked more prominent pain responses in the wildtype mice, while the effect was completely abolished in knockout mice. Conversely, intrathecal administration of l-cysteine lowered visceral pain response in the wildtype mice, and again the effect was completely abolished in the knockout mice. Our study strongly suggests that l-cysteine-mediated modulation of CaV2.3 channels plays an important role in visceral pain processing. Furthermore, our data are consistent with the contrasting roles of CaV2.3 channels in mediating visceral nociception in the peripheral and central pain pathways. [ABSTRACT FROM AUTHOR]

Astrocytes in the adult brain show cellular plasticity; however, whether they have the potential to generate multiple lineages remains unclear. Here, we perform in vivo screens and identify DLX2 as a transcription factor that can unleash the multipotentiality of adult resident astrocytes. Genetic lineage tracing and time-course analyses reveal that DLX2 enables astrocytes to rapidly become ASCL1+ neural progenitor cells, which give rise to neurons, astrocytes, and oligodendrocytes in the adult mouse striatum. Single-cell transcriptomics and pseudotime trajectories further confirm a neural stem cell-like behavior of reprogrammed astrocytes, transitioning from quiescence to activation, proliferation, and neurogenesis. Gene regulatory networks and mouse genetics identify and confirm key nodes mediating DLX2-dependent fate reprogramming. These include activation of endogenous DLX family transcription factors and suppression of Notch signaling. Such reprogramming-induced multipotency of resident glial cells may be exploited for neural regeneration. [ABSTRACT FROM AUTHOR]

Mice have emerged as one of the most popular and valuable model organisms in the research of human biology. This is due to their genetic and physiological similarity to humans, short generation times, availability of genetically homologous inbred strains, and relatively easy laboratory maintenance. Therefore, following the release of the initial human reference genome, the generation of the mouse reference genome was prioritised and represented an important scientific resource for the mouse genetics community. In 2002, the Mouse Genome Sequencing Consortium published an initial draft of the mouse reference genome which contained ~ 96% of the euchromatic genome of female C57BL/6 J mice. Almost two decades on from the publication of the initial draft, sequencing efforts have continued to increase the completeness and accuracy of the C57BL/6 J reference genome alongside advances in genome annotation. Additionally new sequencing technologies have provided a wealth of data that has added to the repertoire of annotations associated with traditional genomic annotations. Including but not limited to advances in regulatory elements, the 3D genome and individual cellular states. In this review we focus on the reference genome C57BL/6 J and summarise the different aspects of genomic and cellular annotations, as well as their relevance to mouse genetic research. We denote a genomic annotation as a functional unit of the genome. Cellular annotations are annotations of cell type or state, defined by the transcriptomic expression profile of a cell. Due to the wide-ranging number and diversity of annotations describing the mouse genome, we focus on gene, repeat and regulatory element annotation as well as two relatively new technologies; 3D genome architecture and single-cell sequencing outlining their utility in genetic research and their current challenges. [ABSTRACT FROM AUTHOR]

The assembled and annotated genomes for 16 inbred mouse strains (Lilue et al., Nat Genet 50:1574–1583, 2018) and two wild-derived strains (CAROLI/EiJ and PAHARI/EiJ) (Thybert et al., Genome Res 28:448–459, 2018) are valuable resources for mouse genetics and comparative genomics. We developed the multiple genome viewer (MGV; http://www.informatics.jax.org/mgv) to support visualization, exploration, and comparison of genome annotations within and across these genomes. MGV displays chromosomal regions of user-selected genomes as horizontal tracks. Equivalent features across the genome tracks are highlighted using vertical 'swim lane' connectors. Navigation across the genomes is synchronized as a researcher uses the scroll and zoom functions. Researchers can generate custom sets of genes and other genome features to be displayed in MGV by entering genome coordinates, function, phenotype, disease, and/or pathway terms. MGV was developed to be genome agnostic and can be used to display homologous features across genomes of different organisms. [ABSTRACT FROM AUTHOR]

The introduction of the CRISPR-Cas9 system in 2013 has revolutionized experimental genetics in mice and rats. This commentary gives an overview on the use of CRISPR either for gene editing in the germline or for editing and beyond editing in somatic cells. Future perspectives are opened by emerging CRISPR technologies that could enable genome engineering at larger scale. [ABSTRACT FROM AUTHOR]

Genetically diverse pluripotent stem cells display varied, heritable responses to differentiation cues. Here, we harnessed these disparities through derivation of mouse embryonic stem cells from the BXD genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, to identify loci regulating cell state transitions. Upon transition to formative pluripotency, B6 stem cells quickly dissolved naïve networks adopting gene expression modules indicative of neuroectoderm lineages, whereas D2 retained aspects of naïve pluripotency. Spontaneous formation of embryoid bodies identified divergent differentiation where B6 showed a propensity toward neuroectoderm and D2 toward definitive endoderm. Genetic mapping identified major trans‐acting loci co‐regulating chromatin accessibility and gene expression in both naïve and formative pluripotency. These loci distally modulated occupancy of pluripotency factors at hundreds of regulatory elements. One trans‐acting locus on Chr 12 primarily impacted chromatin accessibility in embryonic stem cells, while in epiblast‐like cells, the same locus subsequently influenced expression of genes enriched for neurogenesis, suggesting early chromatin priming. These results demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome. SYNOPSIS: The molecular basis for phenotypic variation of embryonic stem cells (ESC) from genetically diverse individuals remains largely unknown. This study combines extensive expression profiling and mouse genetics to identify trans‐acting loci differentially regulating the epigenome during ESC differentiation. Genetic background alters ESC fate and position along the pluripotency spectrum.Genetic background determines ESC differentiation propensity through chromatin regulation in naïve pluripotency.Cellular systems genetics identifies six trans‐acting loci regulating gene expression and chromatin organization.KRAB zinc‐finger protein expression is strain‐dependent, and linked to TRIM28 function at trans‐target genes. [ABSTRACT FROM AUTHOR]

The tremendous public health problem created by substance use disorders (SUDs) presents a major opportunity for mouse genetics. Inbred mouse strains exhibit substantial and heritable differences in their responses to drugs of abuse (DOA) and in many of the behaviors associated with susceptibility to SUD. Therefore, genetic discoveries emerging from analysis of murine genetic models can provide critically needed insight into the neurobiological effects of DOA, and they can reveal how genetic factors affect susceptibility drug addiction. There are already indications, emerging from our prior analyses of murine genetic models of responses related to SUDs that mouse genetic models of SUD can provide actionable information, which can lead to new approaches for alleviating SUDs. Lastly, we consider the features of murine genetic models that enable causative genetic factors to be successfully identified; and the methodologies that facilitate genetic discovery. [ABSTRACT FROM AUTHOR]

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Parent-of-origin-specific expression of imprinted genes is critical for successful mammalian growth and development. Insulin, coded by the INS gene, is an important growth factor expressed from the paternal allele in the yolk sac placenta of therian mammals. The tyrosine hydroxylase gene TH encodes an enzyme involved in dopamine synthesis. TH and INS are closely associated in most vertebrates, but the mouse orthologues, Th and Ins2, are separated by repeated DNA. In mice, Th is expressed from the maternal allele, but the parental origin of expression is not known for any other mammal so it is unclear whether the maternal expression observed in the mouse represents an evolutionary divergence or an ancestral condition. We compared the length of the DNA segment between TH and INS across species and show that separation of these genes occurred in the rodent lineage with an accumulation of repeated DNA. We found that the region containing TH and INS in the tammar wallaby produces at least five distinct RNA transcripts: TH, TH-INS1, TH-INS2, lncINS and INS. Using allele-specific expression analysis, we show that the TH/INS locus is expressed from the paternal allele in pre- and postnatal tammar wallaby tissues. Determining the imprinting pattern of TH/INS in other mammals might clarify if paternal expression is the ancestral condition which has been flipped to maternal expression in rodents by the accumulation of repeat sequences., (© 2024. The Author(s).)

Background: Genetically modified mice are used widely to explore mechanisms in most biomedical fields—including transfusion. Concluding that a gene modification is responsible for a phenotypic change assumes no other differences between the gene‐modified and wild‐type mice besides the targetted gene. Study Design and Methods: To test the hypothesis that the N‐terminus of Band3, which regulates metabolism, affects RBC storage biology, RBCs from mice with a modified N‐terminus of Band3 were stored under simulated blood bank conditions. All strains of mice were generated with the same initial embryonic stem cells from 129 mice and each strain was backcrossed with C57BL/6 (B6) mice. Both 24‐h recoveries post‐transfusion and metabolomics were determined for stored RBCs. Genetic profiles of mice were assessed by a high‐resolution SNP array. Results: RBCs from mice with a mutated Band3 N‐terminus had increased lipid oxidation and worse 24‐h recoveries, "demonstrating" that Band3 regulates oxidative injury during RBC storage. However, SNP analysis demonstrated variable inheritance of 129 genetic elements between strains. Controlled interbreeding experiments demonstrated that the changes in lipid oxidation and some of the decreased 24‐hr recovery were caused by inheritance of a region of chromosome 1 of 129 origin, and not due to the modification of Band 3. SNP genotyping of a panel of commonly used commercially available KO mice showed considerable 129 contamination, despite wild‐type B6 mice being listed as the correct control. Discussion Thousands of articles published each year use gene‐modified mice, yet genetic background issues are rarely considered. Assessment of such issues are not, but should become, routine norms of murine experimentation. [ABSTRACT FROM AUTHOR]

Different types of tissue injury, such as inflammatory and neuropathic conditions, cause modality-specific alternations on temperature perception. There are profound changes in peripheral sensory neurons after injury, but how patterned neuronal activities in the CNS encode injury-induced sensitization to temperature stimuli is largely unknown. Using in vivo calcium imaging and mouse genetics, we show that formalin- and prostaglandin E2-induced inflammation dramatically increase spinal responses to heating and decrease responses to cooling in male and female mice. The reduction of cold response is largely eliminated on ablation of TRPV1-expressing primary sensory neurons, indicating a crossover inhibition of cold response from the hyperactive heat inputs in the spinal cord. Interestingly, chemotherapy medication oxaliplatin can rapidly increase spinal responses to cooling and suppress responses to heating. Together, our results suggest a push-pull mechanism in processing cold and heat inputs and reveal a synergic mechanism to shift thermosensation after injury. [ABSTRACT FROM AUTHOR]

Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying cis-regulatory logics that orchestrate the spatio-temporal Grem1 expression dynamics during limb bud development. We establish that transcript levels are controlled in an additive manner while spatial regulation requires synergistic interactions among multiple enhancers. Disrupting these interactions shows that altered spatial regulation rather than reduced Grem1 transcript levels prefigures digit fusions and loss. Two of the enhancers are evolutionary ancient and highly conserved from basal fishes to mammals. Analysing these enhancers from different species reveal the substantial spatial plasticity in Grem1 regulation in tetrapods and basal fishes, which provides insights into the fin-to-limb transition and evolutionary diversification of pentadactyl limbs. The BMP antagonist Gremlin1 balances BMP and SHH signalling, endowing limb bud development with robustness. Here, the authors identify enhancers controlling Grem1 levels in an additive, and spatial regulation in a synergistic manner, providing digit patterning with cis-regulatory robustness and evolutionary plasticity. [ABSTRACT FROM AUTHOR]

Sirtuin 1 (SIRT1), the NAD-dependent histone deacetylase, has been extensively investigated due to its cognitive protective effect. Studies suggest microRNAs (miRNAs) and histone modifications are key epigenetic regulators of gene expression and play important role in brain development. We previously showed that cognitive impairment by lead (Pb) was associated with downregulation of SIRT1, but the epigenetic role of this is unclear. Thus, we exposed 4-week-old male mice to 0.2% lead acetate solution for three months, and subsequently extracted brain homogenate from mice cortex and hippocampus at the age of 1, 4, and 16 months, respectively. In this study, we found that the protein level of SIRT1 was inhibited in the hippocampus and cortex of 16-month-old aged mice exposed to Pb. Moreover, changes in the levels of miR-138-5p and miR-141-3p, which were considered to the mechanistic target of SIRT1 by bioinformatic analysis, were negative correlations SIRT1 protein expression. We also found miR-34c-3p expression was increased in the cortex of mice at the age of 16 months. Collectively, our results showed the expression of neural SIRT1 and three selected microRNAs at different age nodes of mice for the first time of following Pb exposure. Our results suggest that additional efforts should focus on the consequences of early Pb exposure from an epigenetic perspective. [ABSTRACT FROM AUTHOR]

The genomes of inbred mice harbor around 50 endogenous murine leukemia virus (MLV) loci, although the specific complement varies greatly between strains. The Gv1 locus is known to control the transcription of endogenous MLVs and to be the dominant determinant of cell-surface presentation of MLV envelope, the GIX antigen. Here, we identify a single Krüppel-associated box zinc finger protein (ZFP) gene, Zfp998 , as Gv1 and show it to be necessary and sufficient to determine the G IX + phenotype. By long-read sequencing of bacterial artificial chromosome clones from 129 mice, the prototypic G IX + strain, we reveal the source of sufficiency and deficiency as splice-acceptor variations and highlight the varying origins of the chromosomal region encompassing Gv1. Zfp998 becomes the second identified ZFP gene responsible for epigenetic suppression of endogenous MLVs in mice and further highlights the prominent role of this gene family in control of endogenous retroviruses. [ABSTRACT FROM AUTHOR]

• Existing findings suggest a critical role for the cerebellum in the pathophysiology of autism spectrum disorder (ASD). • We here discuss recent studies on the connection between cerebellar dysfunction and ASD. • We summarize mouse genetics used for studying the relationship between cerebellar dysfunction and ASD-related behaviors. • We raise several intriguing questions needed to be investigated in future. The cerebellum has long been conceptualized to control motor learning and motor coordination. However, increasing evidence suggests its roles in cognition and emotion behaviors. In particular, the cerebellum has been recognized as one of key brain regions affected in autism spectrum disorder (ASD). To better understand the contribution of the cerebellum in ASD pathogenesis, we here discuss recent behavioral, genetic, and molecular studies from the human and mouse models. In addition, we raise several questions that need to be investigated in future studies from the point view of cerebellar dysfunction, cerebro-cerebellar connectivity and ASD. [ABSTRACT FROM AUTHOR]

DNA mismatch repair (MMR) proteins play an important role in maintaining genome stability, both in somatic and in germline cells. Loss of MLH1, a central MMR protein, leads to infertility and to microsatellite instability (MSI) in spermatocytes, however, the effect of Mlh1 heterozygosity on germline genome stability remains unexplored. To test the effect of Mlh1 heterozygosity on MSI in mature sperm, we combined mouse genetics with single-molecule PCR that detects allelic changes at unstable microsatellites. We discovered 4.5% and 5.9% MSI in sperm of 4- and 12-month-old Mlh1 +/− mice, respectively, and that Mlh1 promoter methylation in Mlh1 +/− sperm correlated with higher MSI. No such elevated MSI was seen in non-proliferating somatic cells. Additionally, we show contrasting dynamics of deletions versus insertions at unstable microsatellites (mononucleotide repeats) in sperm. [ABSTRACT FROM AUTHOR]

Dynamic chemical modifications of RNA represent novel and fundamental mechanisms that regulate stemness and tissue homeostasis. Rejuvenation and wound repair of mammalian skin are sustained by epidermal progenitor cells, which are localized within the basal layer of the skin epidermis. N6‐methyladenosine (m6A) is one of the most abundant modifications found in eukaryotic mRNA and lncRNA (long noncoding RNA). In this report, we survey changes of m6A RNA methylomes upon epidermal differentiation and identify Pvt1, a lncRNA whose m6A modification is critically involved in sustaining stemness of epidermal progenitor cells. With genome‐editing and a mouse genetics approach, we show that ablation of m6A methyltransferase or Pvt1 impairs the self‐renewal and wound healing capability of skin. Mechanistically, methylation of Pvt1 transcripts enhances its interaction with MYC and stabilizes the MYC protein in epidermal progenitor cells. Our study presents a global view of epitranscriptomic dynamics that occur during epidermal differentiation and identifies the m6A modification of Pvt1 as a key signaling event involved in skin tissue homeostasis and wound repair. SYNOPSIS: The impact of RNA modification pathways on skin biology has remained poorly explored. Here, combined mouse genetics and multi‐layered profiling identifies methyltransferase Mettl14‐dependent N6‐methyladenosine (m6A) modification as a critical regulator of epidermal stem cell differentiation and homeostasis. Tissue‐specific depletion of Mettl14 reduces global m6A levels and perturbed skin development.Depletion of Mettl14 decreases epidermal stem cell function.Epidermal differentiation is associated with significant methylome changes in mRNAs and long non‐coding RNAs (lncRNAs).m6A modification on lncRNA Pvt1 enhances its association with MYC and supports epidermal stemness in vivo. [ABSTRACT FROM AUTHOR]

Automated detection of complex animal behaviors remains a challenging problem in neuroscience, particularly for behaviors that consist of disparate sequential motions. Grooming is a prototypical stereotyped behavior that is often used as an endophenotype in psychiatric genetics. Here, we used mouse grooming behavior as an example and developed a general purpose neural network architecture capable of dynamic action detection at human observer-level performance and operating across dozens of mouse strains with high visual diversity. We provide insights into the amount of human annotated training data that are needed to achieve such performance. We surveyed grooming behavior in the open field in 2457 mice across 62 strains, determined its heritable components, conducted GWAS to outline its genetic architecture, and performed PheWAS to link human psychiatric traits through shared underlying genetics. Our general machine learning solution that automatically classifies complex behaviors in large datasets will facilitate systematic studies of behavioral mechanisms. [ABSTRACT FROM AUTHOR]

Mice of the C57BL/6ByJ (B6) strain have higher consumption of sucrose, and stronger peripheral neural responses to it, than do mice of the 129P3/J (129) strain. To identify quantitative trait loci (QTLs) responsible for this strain difference and to evaluate the contribution of peripheral taste responsiveness to individual differences in sucrose intake, we produced an intercross (F2) of 627 mice, measured their sucrose consumption in two-bottle choice tests, recorded the electrophysiological activity of the chorda tympani nerve elicited by sucrose in a subset of F2 mice, and genotyped the mice with DNA markers distributed in every mouse chromosome. We confirmed a sucrose consumption QTL (Scon2, or Sac) on mouse chromosome (Chr) 4, harboring the Tas1r3 gene, which encodes the sweet taste receptor subunit TAS1R3 and affects both behavioral and neural responses to sucrose. For sucrose consumption, we also detected five new main-effect QTLs, Scon6 (Chr2), Scon7 (Chr5), Scon8 (Chr8), Scon3 (Chr9), and Scon9 (Chr15), and an epistatically interacting QTL pair Scon4 (Chr1) and Scon3 (Chr9). No additional QTLs for the taste nerve responses to sucrose were detected besides Scon2 (Tas1r3) on Chr4. Identification of the causal genes and variants for these sucrose consumption QTLs may point to novel mechanisms beyond peripheral taste sensitivity that could be harnessed to control obesity and diabetes. [ABSTRACT FROM AUTHOR]

Epstein Barr virus (EBV) is one of the most successful pathogens in humans with more than 95% of the human adult population persistently infected. EBV infects only humans and threatens these with its potent growth transforming ability that readily allows for immortalization of human B cells in culture. Accordingly, it is also found in around 1-2% of human tumors, primarily lymphomas and epithelial cell carcinomas. Fortunately, however, our immune system has learned to control this most transforming human tumor virus in most EBV carriers, and it requires modification of EBV associated lymphomagenesis and its immune control by either co-infections, such as malaria, Kaposi sarcoma associated herpesvirus (KSHV) and human immunodeficiency virus (HIV), or genetic predispositions for EBV positive tumors to emerge. Some of these can be modelled in humanized mice that, therefore, provide a valuable platform to test curative immunotherapies and prophylactic vaccines against these EBV associated pathologies. [ABSTRACT FROM AUTHOR]