Search

Cell migration is fundamental to both development and adult physiology, including gastrulation, brain development, angiogenesis, wound healing, bone remodeling, tissue homeostasis, and the immune response. Additionally, misguided cellular migration is implicated in disease pathologies such as cancer metastasis and fibrosis. The microenvironment influences cell migration modes such as mesenchymal, amoeboid, lobopodial, and collective, and these are governed through local signaling by affecting the gene expression and epigenetic alteration of migration-related genes. Plasticity in switching between migration modes is essential for key cellular processes across various contexts. Understanding the mechanisms of cell migration modes and its plasticity is essential for unraveling the complexities of this process and revealing its implications in physiological and pathological contexts. This review focuses on different modes of cell migration, including their aberrant migration in disease pathologies and how they can be therapeutically targeted in disease conditions such as cancer. [ABSTRACT FROM AUTHOR]

Up to 80% of children with autism spectrum disorder have at least one other neuropsychiatric comorbidity. The causes of such disorders are highly genetic, yet many studies fail to take analysis further than risk gene discovery to see cellular and mechanistic changes occurring. Therefore, the goal of this study was to unveil novel gene expression signatures involved in important neurodevelopmental processes that, when disrupted, lead to each of the autism comorbidities of interest. We achieved this by analysing a single‐nuclei RNA sequencing dataset with prefrontal cortex samples from autism spectrum disorder plus comorbidities for differentially expressed genes. The highest number of alterations was seen in excitatory neurons, which also showed differential population and cell–cell interactions across disorders and an increase in expression of genes involved in neurodevelopmental pathways. Interestingly, the group without comorbidities displayed an increase in neuron–neuron interactions yet a decrease in population number, suggesting a major rewiring of neuronal connections. Further analysis of the topmost significant genes from this cell type in developing prefrontal cortex datasets revealed interesting expression trajectories corresponding to important time points during corticogenesis. This further identified four novel candidate genes that show a potential link to developmental pathways that may contribute to autism and its comorbidities when dysregulated. The study provides a better understanding of co‐occurring conditions at a transcriptomic and cell‐type level and thereby aid future research in providing earlier diagnosis, care and intervention. [ABSTRACT FROM AUTHOR]

Wheat is one of the most important cereal crops for the global food security. Due to its narrow genetic base, modern bread wheat cultivars face challenges from increasing abiotic and biotic stresses. Since genetic improvement is the most sustainable approach, finding novel genes and alleles is critical for enhancing the genetic diversity of wheat. The tertiary gene pool of wheat is considered a gold mine for genetic diversity as novel genes and alleles can be identified and transferred to wheat cultivars. Aegilops geniculata and Ae. umbellulata are the key members of the tertiary gene pool of wheat and harbor important genes against abiotic and biotic stresses. Homoeologous-group five chromosomes (5Uu and 5Mg) have been extensively studied from Ae. geniculata and Ae. umbellulata as they harbor several important genes including Lr57, Lr76, Yr40, Yr70, Sr53 and chromosomal pairing loci. In the present study, using chromosome DNA sequencing and RNAseq datasets, we performed comparative analysis to study homoeologous gene evolution in 5Mg, 5Uu, and group 5 wheat chromosomes. Our findings highlight the diversity of transcription factors and resistance genes, resulting from the differential expansion of the gene families. Both the chromosomes were found to be enriched with the "response to stimulus" category of genes providing resistance against biotic and abiotic stress. Phylogenetic study positioned the M genome closer to the D genome, with higher proximity to the A genome than the B genome. Over 4000 genes were impacted by SNPs on 5D, with 4-5% of those genes displaying nondisruptive variations that affect gene function. [ABSTRACT FROM AUTHOR]

There remains an urgent need for new therapies for treatment-resistant epilepsy. Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bidirectional control of sodium channel expression are needed. MicroRNAs (miRNA) are small noncoding RNAs which negatively regulate gene expression. Here we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the antiseizure medicine cannabidiol, and plasma from patients with treatment-resistant epilepsy, converge on a single target—miR-335- 5p. Pathway analysis on predicted and validated miR-335- 5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335- 5p resulted in upregulation of Scn1a, Scn2a, and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335- 5p. Blocking miR-335- 5p also increased voltage-gated sodium currents and SCN1A, SCN2A, and SCN3A expression in human induced pluripotent stem cell-derived neurons. Inhibition of miR-335- 5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazol seizure model, whereas adeno-associated virus 9-mediated overexpression of miR-335- 5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335- 5p may be a means to regulate VGSCs and affect neuronal excitability and seizures. Changes to miR-335- 5p may reflect compensatory mechanisms to control excitability and could provide biomarker or therapeutic strategies for different types of treatment-resistant epilepsy. [ABSTRACT FROM AUTHOR]

The human brain is divided into various anatomical regions that control and coordinate unique functions. The prefrontal cortex (PFC) is a large brain region that comprises a range of neuronal and non-neuronal cell types, sharing extensive interconnections with subcortical areas, and plays a critical role in cognition and memory. A timely appearance of distinct cell types through embryonic development is crucial for an anatomically perfect and functional brain. Direct tracing of cell fate development in the human brain is not possible, but single-cell transcriptome sequencing (scRNA-seq) datasets provide the opportunity to dissect cellular heterogeneity and its molecular regulators. Here, using scRNA-seq data of human PFC from fetal stages, we elucidate distinct transient cell states during PFC development and their underlying gene regulatory circuitry. We further identified that distinct intermediate cell states consist of specific gene regulatory modules essential to reach terminal fate using discrete developmental paths. Moreover, using in silico gene knock-out and over-expression analysis, we validated crucial gene regulatory components during the lineage specification of oligodendrocyte progenitor cells. Our study illustrates unique intermediate states and specific gene interaction networks that warrant further investigation for their functional contribution to typical brain development and discusses how this knowledge can be harvested for therapeutic intervention in challenging neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Activating invasion and metastasis are one of the primary hallmarks of cancer, the latter representing the leading cause of death in cancer patients. Whilst many advances in this area have been made in recent years, the process of cancer dissemination and the underlying mechanisms governing invasion are still poorly understood. Cancer cells exhibit multiple invasion strategies, including switching between modes of invasion and plasticity in response to therapies, surgical interventions and environmental stimuli. The ability of cancer cells to switch migratory modes and their inherent plasticity highlights the critical challenge preventing the successful design of cancer and anti-metastatic therapies. This mini-review presents current knowledge on the critical models of tumour invasion and dissemination. We also discuss the current issues surrounding current treatments and arising therapeutic opportunities. We propose that the establishment of novel approaches to study the key biological mechanisms underlying the metastatic cascade is critical in finding novel targets that could ultimately lead to complete inhibition of cancer cell invasion and dissemination. [ABSTRACT FROM AUTHOR]

Over two billion people, depending largely on staple foods, suffer from deficiencies in protein and some micronutrients such as iron and zinc. Among various approaches to overcome protein and micronutrient deficiencies, biofortification through a combination of conventional and molecular breeding methods is the most feasible, cheapest, and sustainable approach. An interspecific cross was made between the wheat cultivar 'Chinese Spring' and Aegilops kotschyi Boiss. accession 396, which has a threefold higher grain iron and zinc concentrations and about 33% higher protein concentration than wheat cultivars. Recurrent backcrossing and selection for the micronutrient content was performed at each generation. Thirteen derivatives with high grain iron and zinc concentrations and contents, ash and ash micronutrients, and protein were analyzed for alien introgression. Morphological markers, high molecular weight glutenin subunit profiles, anchored wheat microsatellite markers, and GISH showed that addition and substitution of homoeologous groups 1, 2, and 7 chromosomes of Ae. kotschyi possess gene(s) for high grain micronutrients. The addition of 1U/1S had high molecular weight glutenin subunits with higher molecular weight than those of wheat, and the addition of 2S in most of the derivatives also enhanced grain protein content by over 20%. Low grain protein content in a derivative with a 2S-wheat translocation, waxy leaves, and absence of the gdm148 marker strongly suggests that the gene for higher grain protein content on chromosome 2S is orthologous to the grain protein QTL on the short arm of group 2 chromosomes. Key words: wheat, Aegilops kotschyi, grain iron, grain zinc, grain protein, microsatellite markers, HMW-glutenin subunits, genomic in situ hybridization. Plus de deux milliards de personnes qui se nourrissent principalement d'aliments de base souffrent de deficiences en proteines et certains micronutriments comme le fer et le zinc. Parmi diverses approches visant a palier ces deficiences en proteines et en micronutriments, la biofortification via une combinaison de methodes moleculaires et conventionnelles d' amelioration genetique constitue l'approche la plus realisable, economique et durable. Un croisement interspecifique a ete realise entre le ble 'Chinese Spring' et l'accession 396 de l'Aegilops kotschyi, dont les grains ont une teneur en fer et en zinc trois fois plus elevee et une teneur en proteine superieure de 33 % a la concentration rencontree chez les cultivars de ble. Des retrocroisements ont ete realises a repetition avec selection pour le contenu en micronutriments a chaque generation. Treize lignees derivees avec une forte teneur en zinc et en fer ont ete analysees pour la teneur en cendres et la concentration en zinc, fer et proteines dans les cendres. Des marqueurs morphologiques, le profil des glutenines HMW, des marqueurs microsatellites d ancrage et des analyses GISH ont revele l'addition et la substitution d homeologues des groupes 1, 2 et 7 de l'Ae. kotschyi, lesquels porteraient un ou des genes conferant une plus haute teneur en micronutriments chez les grains. L'addition 1U/1S se traduisait par des glutenines HMW de plus grande taille que chez le ble tandis que l'addition du chromosome 2S entrainait chez la majorite des lignees un accroissement de plus de 20% de la teneur en proteines. La faible teneur en proteine chez une lignee portant une translocation 2S-ble, la caractere cireux des feuilles et l'absence du marqueur gdm148 suggerent fortement que le gene qui confere une plus haute teneur en proteine sur 2S serait l'orthologue du QTL pour la teneur en proteine des grains qui est situe sur le bras courte des chromosomes du groupe 2. Mots-cles : ble, Aegilops kotschyi, teneur en fer des grains, teneur en zinc des grains, teneur ne proteine des grains, marqueurs microsatellites, sous-unites HMW des glutenines, hybridation genomique in situ. [Traduit par la Redaction], Introduction More than half of the world's population suffers from iron and zinc deficiencies and more than 160 million children under the age of five lack adequate protein intake (WHO [...]

Synthetic amphiploids are the immortal sources for studies on crop evolution, genome dissection, and introgression of useful variability from related species. Cytological analysis of synthetic decaploid wheat (Triticum aestivum L.)-- Aegilops kotschyi Boiss. amphiploids (AABBDD[U.sup.k][U.sup.k][S.sup.k][S.sup.k]) showed some univalents from the [C.sub.1] generation onward followed by chromosome elimination. Most of the univalents came to metaphase I plate after the reductional division of paired chromosomes and underwent equational division leading to their elimination through laggards and micronuclei. Substantial variation in the chromosome number of pollen mother cells from different tillers, spikelets, and anthers of some plants also indicated somatic chromosome elimination. Genomic in situ hybridization, fluorescence in situ hybridization, and simple sequence repeat markers analysis of two amphiploids with reduced chromosomes indicated random chromosome elimination of various genomes with higher sensitivity of D followed by the [S.sup.k] and [U.sup.k] genomes to elimination, whereas 1D chromosome was preferentially eliminated in both the amphiploids investigated. One of the partial amphiploids, [C.sub.4] T. aestivum 'Chinese Spring' -Ae. kotschyi 396 (2n = 58), with 34 T. aestivum, 14 [U.sup.k], and 10 [S.sup.k] had stable meiosis and high fertility. The partial amphiploids with white glumes, bold seeds, and tough rachis with high grain macroand micronutrients and resistance to powdery mildew could be used for T. aestivum biofortification and transfer of powdery mildew resistance. Key words: Partial amphiploid, chromosome elimination, grain iron, grain zinc, powdery mildew resistance, in situ hybridization. Les amphiploides synthetiques constituent des ressources immortelles pour des etudes portant sur revolution des cultures, la dissection des genomes et l'introgression de variabilite utile provenant d'especes apparentees. Une analyse cytogeenetique d'amphiploides deecaploldes (Triticum aestivum L.)-- Aegilops kotschyi Boiss. (AABBDD[U.sup.k][U.sup.k][S.sup.k][S.sup.k]) a permis d'observer des univalents a compter de la generation [C.sub.1] suivie d'eelimination chromosomique. La plupart des univalents ont atteint la plaque de la metaphase I apres la division reductionnelle des chromosomes appariees et ont subi la division equationnelle qui a mene a leur elimination sous forme de chromosomes retardataires ou de micronoyaux. Une variation substantielle du nombre de chromosomes observes chez les microsporocytes provenant de diffeerents eepis, epillets et antheres chez certaines plantes suggere qu'il se produirait egalement de l'elimination chromosomique au niveau somatique. Des analyses GISH, FISH et de marqueurs SSR sur deux amphiploides avec un nombre reduit de chromosomes a indique que l'elimination chromosomique etait aleatoire au sein des diffeerents genomes. Globalement, le genome D, suivi des genomes [S.sup.k] et [U.sup.k],etait le plus souvent sujet a elimination et le chromosome 1D avait ete preferentiellement perdu chez les deux amphiploides examines. Un des amphiploides partiels de generation [C.sub.4], 'Chinese Spring'--Ae. kotschyi 396 (2n = 58), comptait 34 chromosomes du T. aestivum, 14 du genome [U.sup.k] et 10 du genome [S.sup.k] et il presentait une meeiose stable ainsi qu'une fecondite eeleveee. Les amphiploides partiels a glumes blanches, gros grains, rachis resistant, forte teneur en micro- et macronutriments ainsi que resistants a l'oidium pourraient s'aveerer utiles pour l'ameelioration de la valeur nutritive du T. aestivum et le transfert de resistance a l'oidium. Mots-cles: amphiploide partiel, elimination chromosomique, teneur en fer dans les grains, teneur en zinc dans les grains, resistance a l'oidium, hybridation in situ. [Traduit par la Redaction], Introduction Alloploidy through interspecific hybridization and spontaneous doubling of chromosomes has played a major role in speciation and genome evolution of higher plants (Slotis and Slotis 1999; Feldman and Levy [...]

Abstract: Four different interspecific hybrids involving three different accessions of Aegilops longissima Schweinf. & Muschl. with high grain iron and zinc content and three Triticum turgidum L. subsp. durum (Desf.) [...]

Corticogenesis consists of a series of synchronised events, including fate transition of cortical progenitors, neuronalmigration, specification and connectivity. NeuroD1, a basic helix-loop-helix (bHLH) transcription factor (TF), contributes to all of these events, but how it coordinates these independently is still unknown. Here, we demonstrate that NeuroD1 expression is accompanied by a gain of active chromatin at a large number of genomic loci. Interestingly, transcriptional activation of these loci relied on a high local density of adjacent bHLH TFsmotifs, including, predominantly, Tcf12.We found that activity and expression levels of Tcf12 were high in cells with induced levels of NeuroD1 that spanned the transition of cortical progenitors from proliferative to neurogenic divisions. Moreover, Tcf12 forms a complex with NeuroD1 and co-occupies a subset of NeuroD1 target loci. This Tcf12-NeuroD1 cooperativity is essential for gaining active chromatin and targeted expression of genes involved in cell migration. By functional manipulation in vivo, we further show that Tcf12 is essential during cortical development for the correct migration of newborn neurons and, hence, for proper cortical lamination. [ABSTRACT FROM AUTHOR]

The multistep process of epithelial-to-mesenchymal transition (EMT), whereby static epithelial cells become migratory mesenchymal cells, plays a critical role during various developmental contexts, wound healing, and pathological conditions such as cancer metastasis. Despite the established function of basic helix-loop-helix (bHLH) transcription factors (TFs) in cell fate determination, only a few have been examined for their role in EMT. Here, using transcriptome analysis of distinct stages during stepwise progression of transforming growth factor beta (TGF b)-induced EMT in mammary epithelial cells, we revealed distinct categories of bHLH TFs that show differential expression kinetics during EMT. Using a short interfering RNA-mediated functional screen for bHLH TFs during EMT, we found Max network transcription repressor (MNT) to be essential for EMT in mammary epithelial cells. We show that the depletion of MNT blocks TGF b-induced morphological changes during EMT, and this is accompanied by derepression of a large number of epithelial genes. We show that MNT mediates the repression of epithelial identity genes during EMT by recruiting HDAC1 and mediating the loss of H3K27ac and chromatin accessibility. Lastly, we show that MNT is expressed at higher levels in EMT-High breast cancer cells and is required for their migration. Taken together, these findings establish MNT as a critical regulator of cell fate changes during mammary EMT. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms are known to define cell-type identity and function. Hence, reprogramming of one cell type into another essentially requires a rewiring of the underlying epigenome. Cellular reprogramming can convert somatic cells to induced pluripotent stem cells (iPSCs) that can be directed to differentiate to specific cell types. Trans-differentiation or direct reprogramming, on the other hand, involves the direct conversion of one cell type into another. In this review, we highlight how gene regulatory mechanisms identified to be critical for developmental processes were successfully used for cellular reprogramming of various cell types. We also discuss how the therapeutic use of the reprogrammed cells is beginning to revolutionize the field of regenerative medicine particularly in the repair and regeneration of damaged tissue and organs arising from pathological conditions or accidents. Lastly, we highlight some key challenges hindering the application of cellular reprogramming for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Abstract Background The uneven distribution of recombination across the length of chromosomes results in inaccurate estimates of genetic to physical distances. In wheat (Triticum aestivum L.) chromosome 3B, it has been estimated that 90% of the cross over events occur in distal sub-telomeric regions representing 40% of the chromosome. Radiation hybrid (RH) mapping which does not rely on recombination is a strategy to map genomes and has been widely employed in animal species and more recently in some plants. RH maps have been proposed to provide i) higher and ii) more uniform resolution than genetic maps, and iii) to be independent of the distribution patterns observed for meiotic recombination. An in vivo RH panel was generated for mapping chromosome 3B of wheat in an attempt to provide a complete scaffold for this ~1 Gb segment of the genome and compare the resolution to previous genetic maps. Results A high density RH map with 541 marker loci anchored to chromosome 3B spanning a total distance of 1871.9 cR was generated. Detailed comparisons with a genetic map of similar quality confirmed that i) the overall resolution of the RH map was 10.5 fold higher and ii) six fold more uniform. A significant interaction (r = 0.879 at p = 0.01) was observed between the DNA repair mechanism and the distribution of crossing-over events. This observation could be explained by accepting the possibility that the DNA repair mechanism in somatic cells is affected by the chromatin state in a way similar to the effect that chromatin state has on recombination frequencies in gametic cells. Conclusions The RH data presented here support for the first time in vivo the hypothesis of non-casual interaction between recombination hot-spots and DNA repair. Further, two major hypotheses are presented on how chromatin compactness could affect the DNA repair mechanism. Since the initial RH application 37 years ago, we were able to show for the first time that the iii) third hypothesis of RH mapping might not be entirely correct.

Epithelial to mesenchymal transition (EMT) is the process whereby a polarized epithelial cell ceases to maintain cell-cell contacts, loses expression of characteristic epithelial cell markers, and acquires mesenchymal cell markers and properties such as motility, contractile ability, and invasiveness. A complex process that occurs during development and many disease states, EMT involves a plethora of transcription factors (TFs) and signaling pathways. Whilst great advances have been made in both our understanding of the progressive cell-fate changes during EMT and the gene regulatory networks that drive this process, there are still gaps in our knowledge. Epigenetic modifications are dynamic, chromatin modifying enzymes are vast and varied, transcription factors are pleiotropic, and signaling pathways are multifaceted and rarely act alone. Therefore, it is of great importance that we decipher and understand each intricate step of the process and how these players at different levels crosstalk with each other to successfully orchestrate EMT. A delicate balance and fine-tuned cooperation of gene regulatory mechanisms is required for EMT to occur successfully, and until we resolve the unknowns in this network, we cannot hope to develop effective therapies against diseases that involve aberrant EMT such as cancer. In this review, we focus on data that challenge these unknown entities underlying EMT, starting with EMT stimuli followed by intracellular signaling through to epigenetic mechanisms and chromatin remodeling. [ABSTRACT FROM AUTHOR]

Aegilops tauschii (2n = 2x = 14, genome DD), also known as Tausch's goatgrass, is the D genome donor of bread or hexaploid wheat Triticum aestivum (2n = 2x = 42, AABBDD genome). It is a rich reservoir of useful genes for biotic and abiotic stress tolerance for wheat improvement. We developed a TILLING (Targeting Induced Local Lesions In Genomes) resource for Ae. tauschii for discovery and validation of useful genes in the D genome of wheat. The population, referred to as TILL-D, was developed with ethyl methanesulfonate (EMS) mutagen. The survival rate in M1 generation was 73%, out of which 22% plants were sterile. In the M2 generation 25% of the planted seeds showed phenotypic mutations such as albinos, chlorinas, no germination, variegated, sterile and partially fertile events, and 2,656 produced fertile M2 plants. The waxy gene was used to calculate the mutation frequency (1/70 kb) of the developed population, which was found to be higher than known mutation frequencies for diploid plants (1/89–1/1000 kb), but lower than that for a polyploid species (1/24–1/51 kb). The TILL-D resource, together with the newly published Ae. tauschii reference genome sequence, will facilitate gene discoveries and validations of agronomically important traits and their eventual fine transfer in bread wheat. [ABSTRACT FROM AUTHOR]

Abstract: Tan spot, caused by a necrotrophic fungus Pyrenophora tritici‐repentis (Ptr), has become an important foliar disease of wheat worldwide. Effective control of tan spot can be achieved by deployment of resistant wheat cultivars. An F2:3 population derived from a cross between synthetic hexaploid wheat (SHW), TA4161‐L1 (moderately resistant) and susceptible winter wheat cultivar, ‘TAM105’ was evaluated with race 1 of Ptr under controlled conditions. The population was genotyped using Diversity Arrays Technology (DArT). Presence of transgressive segregants indicated contribution of positive alleles from both parents. Two major QTLs were located on the short arm of chromosomes 1A and 6A and designated as QTs.ksu‐1A and QTs.ksu‐6A, respectively. Two additional QTLs were identified on chromosome 7A. Resistant alleles of all the QTLs were contributed by TA4161‐L1. Novel QTLs on 6A and 7A can be a valuable addition to known resistance genes and utilized in breeding programmes to produce highly resistant cultivars. [ABSTRACT FROM AUTHOR]

The developing neocortex in the mammalian brain is composed of multiple cell types including apical progenitors (AP), basal progenitors (BP), and neurons that populate three different layers, the ventricular zone (VZ), the subventricular zone (SVZ), and the cortical plate (CP). Despite recent advances, the diversity of the existing cell populations including those which are differentiating and mature, their biogenesis and the underlying gene regulatorymechanisms remain poorly known. Recent studies have taken advantage of the rapidly emerging single-cell technologies to decode the heterogeneity of cell populations at the transcriptome level during cortical development and their molecular details. Here we review these studies and provide an overview of the steps in single-cell transcriptomics including both experimental and computational analysis. We also discuss how single-cell genomics holds a big potential in future for brain research and discuss its possible applications and biological insights that can be achieved from these approaches. We conclude this review by discussing the current challenges in the implementation of single-cell techniques toward a comprehensive understanding of the genetic and epigenetic mechanisms underlying neocortex development. [ABSTRACT FROM AUTHOR]