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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2009.04.001 Byline: Stine Buchmann-MA[cedilla]ller (a)(b), Iris Miescher (a), Nessy John (a)(b), Jaya Krishnan (b), Chu-Xia Deng (c), Lukas Sommer (a) Keywords: Neural crest; Smooth muscle formation; Autonomic neurogenesis; Sensory neurogenesis; Smad4; TGF[beta]; BMP; Cell survival; Proliferation; Fate decision Abstract: During vertebrate development, neural crest cells are exposed to multiple extracellular cues that drive their differentiation into neural and non-neural cell lineages. Insights into the signals potentially involved in neural crest cell fate decisions in vivo have been gained by cell culture experiments that have allowed the identification of instructive growth factors promoting either proliferation of multipotent neural crest cells or acquisition of specific fates. For instance, members of the TGF[beta] factor family induce neurogenesis and smooth muscle cell formation at the expense of other fates in culture. In vivo, conditional ablation of various TGF[beta] signaling components resulted in malformations of non-neural derivatives of the neural crest, but it is unclear whether these phenotypes involved aberrant fate decisions. Moreover, it remains to be shown whether neuronal determination indeed requires TGF[beta] factor activity in vivo. To address these issues, we conditionally deleted Smad4 in the neural crest, thus inactivating all canonical TGF[beta] factor signaling. Surprisingly, neural crest cell fates were not affected in these mutants, with the exception of sensory neurogenesis in trigeminal ganglia. Rather, Smad4 regulates survival of smooth muscle and proliferation of autonomic and ENS neuronal progenitor cells. Thus, Smad signaling plays multiple, lineage-specific roles in vivo, many of which are elicited only after neural crest cell fate decision. Author Affiliation: (a) Division of Cell and Developmental Biology, Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland (b) Institute of Cell Biology, ETH Zurich, CH-8093 Zurich, Switzerland (c) Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA Article History: Received 13 January 2009; Revised 30 March 2009; Accepted 1 April 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2009.01.026 Byline: Greg Holmes (a), Gerson Rothschild (a), Upal Basu Roy (a), Chu-Xia Deng (a)(b), Alka Mansukhani (a), Claudio Basilico (a) Keywords: Fgfr2; Craniosynostosis; Apert syndrome; Osteoblast; Coronal suture; Calvaria; Mouse; Intramembranous ossification Abstract: Activating mutations of FGFRs1-3 cause craniosynostosis (CS), the premature fusion of cranial bones, in man and mouse. The mechanisms by which such mutations lead to CS have been variously ascribed to increased osteoblast proliferation, differentiation, and apoptosis, but it is not always clear how these disturbances relate to the process of suture fusion. We have reassessed coronal suture fusion in an Apert Fgfr2 (S252W) mouse model. We find that the critical event of CS is the early loss of basal sutural mesenchyme as the osteogenic fronts, expressing activated Fgfr2, unite to form a contiguous skeletogenic membrane. A mild increase in osteoprogenitor proliferation precedes but does not accompany this event, and apoptosis is insignificant. On the other hand, the more apical coronal suture initially forms appropriately but then undergoes fusion, albeit at a slower rate, accompanied by a significant decrease in osteoprogenitor proliferation, and increased osteoblast maturation. Apoptosis now accompanies fusion, but is restricted to bone fronts in contact with one another. We correlated these in vivo observations with the intrinsic effects of the activated Fgfr2 S252W mutation in primary osteoblasts in culture, which show an increased capacity for both proliferation and differentiation. Our studies suggest that the major determinant of Fgfr2-induced craniosynostosis is the failure to respond to signals that would halt the recruitment or the advancement of osteoprogenitor cells at the sites where sutures should normally form. Author Affiliation: (a) Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA (b) Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, US National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA Article History: Received 13 November 2008; Revised 16 January 2009; Accepted 20 January 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.02.006 Byline: Xuguang Nie (a), Chu-xia Deng (b), Qin Wang (c), Kai Jiao (a) Keywords: Smad4; Pharyngeal arch; Pharyngeal arch artery; Outflow tract; Facial primordia; Neural crest cells Abbreviations: NC, neural crest; NCCs, neural crest cells; OFT, outflow track; PA, pharyngeal arch; PAA, pharyngeal arch artery Abstract: TGF[beta]/BMP signaling pathways are essential for normal development of neural crest cells (NCCs). Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of TGF[beta]/BMP signaling. In this work, we sought to investigate the roles of Smad4 for development of NCCs. To overcome the early embryonic lethality of Smad4 null mice, we specifically disrupted Smad4 in NCCs using a Cre/loxP system. The mutant mice died at mid-gestation with defects in facial primordia, pharyngeal arches, outflow tract and cardiac ventricles. Further examination revealed that mutant embryos displayed severe molecular defects starting from E9.5. Expression of multiple genes, including Msx1, 2, Ap-2[alpha], Pax3, and Sox9, which play critical roles for NCC development, was downregulated by NCC disruption of Smad4. Moreover, increased cell death was observed in pharyngeal arches from E10.5. However, the cell proliferation rate in these areas was not substantially altered. Taken together, these findings provide compelling genetic evidence that Smad4-mediated activities of TGF[beta]/BMP signals are essential for appropriate NCC development. Author Affiliation: (a) Department of Genetics, Division of Genetic and Translational Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA (b) Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MA 20892, USA (c) Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294, USA Article History: Received 22 February 2007; Revised 31 January 2008; Accepted 5 February 2008

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.01.035 Byline: Motozo Yamashita (1), Sai-Xia Ying (1), Gen-mu Zhang (2), Cuiling Li (3), Steven Y. Cheng (1), Chu-xia Deng (3), Ying E. Zhang (1) Abstract: Bone is constantly resorbed and formed throughout life by coordinated actions of osteoclasts and osteoblasts. Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts. Smurf1-deficient mice are born normal but exhibit an age-dependent increase of bone mass. The cause of this increase can be traced to enhanced activities of osteoblasts, which become sensitized to bone morphogenesis protein (BMP) in the absence of Smurf1. However, loss of Smurf1 does not affect the canonical Smad-mediated intracellular TGF[beta] or BMP signaling; instead, it leads to accumulation of phosphorylated MEKK2 and activation of the downstream JNK signaling cascade. We demonstrate that Smurf1 physically interacts with MEKK2 and promotes the ubiquitination and turnover of MEKK2. These results indicate that Smurf1 negatively regulates osteoblast activity and response to BMP through controlling MEKK2 degradation. Author Affiliation: (1) Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 (2) Laboratory Animal Science Program, National Cancer Institute at Frederick, Frederick, Maryland 21702 (3) Mammalian Genetics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 Article History: Received 9 July 2004; Revised 24 November 2004; Accepted 20 January 2005 Article Note: (miscellaneous) Published: April 7, 2005

Research has been conducted on BRCA1, a breast and ovarian tumor supressor. Results suggest that the lost of this suppressor in female cells will lead to X chromosome perturbation and its silenced state destabilization.

The Smad family of intracellular signaling intermediates transduce signals downstream from the transforming growth factor beta (TGF-[beta]) family of receptor serine threonine kinases. The original member of this family, Smad1, has been shown to mediate signals from receptors for the bone morphogenetic proteins (BMPs), a large group of ligands in the TGF-[beta] superfamily that mediate important developmental events. We have targeted the Smad1 gene in mice and created mutants null at this locus. Smad1 mutant mice die at approximately 9.5 days postcoitum due to defects in allantois formation. In Smad1 mutant mice, the allantois fails to fuse to the chorion, resulting in a lack of placenta and failure to establish a definitive embryonic circulation. Although vasculogenesis is initiated in the mutant allantois, the vessels formed are disorganized, and VCAM-1 protein, a marker for distal allantois development, is not expressed. Smad1 null fibroblasts are still able to respond to BMP2, however, suggesting that the defect observed in the developing extraembryonic tissue is caused by a very specific loss of transcriptional activity regulated by Smad1. Our data further demonstrate that although highly similar structurally, Smad proteins are not functionally homologous. Key Words: TGF-[beta]; Smads; allantois; BMP; targeted mutagenesis; VCAM-1; placenta.

Gene targeting was used to create mice completely deficient for Dv/1, a mouse homolog of the Drosphila segment polarity gene Dishevelled. The mice were viable, fertile and structurally normal, but showed reduced social interaction. Such mutants could therefore act as models for certain human psychiatric disorders.

Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene, which is frequently mutated in breast and ovarian cancers. BRCA1 plays a key role in the homologous recombination directed DNA repair, allowing its deficiency to act as a therapeutic target of DNA damaging agents. In this study, we found that inhibition of the class I histone deacetylases (HDAC) exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells. Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein (TXNIP), causing reactive oxygen species (ROS)-mediated DNA damage. This effect induced preferential apoptosis in BRCA1 −/− breast cancer cells where DNA repair system is compromised. Two animal experiments and gene expression-associated patients' survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC. Finally, the combination of inhibitors of HDAC and bromodomain and extra-terminal motif (BET), another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage, showed a strong anticancer effect in BRCA1 −/− breast cancer cells. Together, this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries, HDAC and BET. Histone deacetylase (HDAC) inhibition upregulates the expression of pro-oxidant protein, thioredoxin interaction protein (TXNIP), leading to reactive oxygen species (ROS) accumulation and high DNA double-strand breaks in cells. Breast cancer susceptibility gene 1 (BRCA1)-deficient breast cancer cells were highly sensitive to HDAC inhibition due to the lack of homologous recombination DNA repair system and hence underwent synthetic lethality. Image 1 [ABSTRACT FROM AUTHOR]

Alternative splicing in the fibroblast growth factor receptor 1 (Fgfr1) locus generates a variety of splicing isoforms, including FGFR1[Alpha] isoforms, which contain three immunoglobulin-like loops in the extracellular domain of the receptor. It has been previously shown that embryos carrying targeted disruptions of all major isoforms die during gastrulation, displaying severe growth retardation and defective mesodermal structures. Here we selectively disrupted the FGFR1[Alpha] isoforms and found that they play an essential role in posterior mesoderm formation during gastrulation. We show that the mutant embryos lack caudal somites, develop spina bifida, and die at 9.5-12.5 days of embryonic development because they are unable to establish embryonic circulation. The primary defect is a failure of axial mesoderm cell migration toward the posterior portions of the embryos during gastrulation, as revealed by regional marker analysis and DiI labeling. In contrast, the anterior migration of the notochord is unaffected and the embryonic structures rostral to the forelimb are relatively normal. These data demonstrate that FGF/FGFR1[Alpha] signals are posteriorizing factors that control node regression and posterior embryonic development. Key Words: gene targeting; FGFR1[Alpha] isoforms; morphogenetic movement; spina bifida.

Summary: Under various conditions, mammals have the ability to maintain serum glucose concentration within a narrow range. SIRT1 plays an important role in regulating gluconeogenesis and fat metabolism; however, the underlying mechanisms remain elusive. Here, we show that SIRT1 forms a complex with FOXO3a and NRF1 on the SIRT6 promoter and positively regulates expression of SIRT6, which, in turn, negatively regulates glycolysis, triglyceride synthesis, and fat metabolism by deacetylating histone H3 lysine 9 in the promoter of many genes involved in these processes. Liver-specific deletion of SIRT6 in mice causes profound alterations in gene expression, leading to increased glycolysis, triglyceride synthesis, reduced β oxidation, and fatty liver formation. Human fatty liver samples exhibited significantly lower levels of SIRT6 than did normal controls. Thus, SIRT6 plays a critical role in fat metabolism and may serve as a therapeutic target for treating fatty liver disease, the most common cause of liver dysfunction in humans. [Copyright &y& Elsevier]

Abstract: Neovascularisation is critical in several malignant and inflammatory conditions, as well as in the course of eye disorders. During new vessel formation, endothelial cell functions, such as proliferation and sprouting are very important and are regulated by a variety of growth factors. The DNA damage response machinery as well as factors regulating histone modifications, such as histone deacetylases, regulate cell fate as well as gene expression. Recent evidence has pointed to potential interactions among BRCA1, H2AX and SIRT1 in these intracellular pathways and neovascularisation, which will be reviewed here. [Copyright &y& Elsevier]

Abstract: RNA interference (RNAi) is a simple and powerful tool widely used to study gene functions in many species. Vector-based systems using RNA polymerase III promoters have been developed to achieve stable expression of small interfering RNA (siRNA) or small hairpin RNA (shRNA) in mammalian cells. Recent investigations demonstrated that when, combined with the Cre-loxP system, the vector-based RNAi can be used to achieve conditional or tissue specific knockdown of endogenous genes with high efficiency in mice. Here, we review these recent progresses and discuss the advantages, limitations and future development of this emerging technology. [Copyright &y& Elsevier]

Summary: Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-β, BMP, or IL-6. Our study uncovers a novel role of TGF-β/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis. [Copyright &y& Elsevier]

Highlights • PP2ACɑ deficiency impairs early brain development. • PP2ACɑ positively regulates the growth of neuronal stem cell. • PP2ACɑ interacts with ATM and ATR in response to DNA damage. • ATM and ATR activate the P53/HIPK2/HIC1 regulation loop. • HIC1 transcriptional regulates HIPK2 gene expression. Abstract The role of protein phosphatase 2ACα (PP2ACα) in brain development is poorly understood. To understand the function of PP2ACα in neurogenesis, we inactivated P p2 acα gene in the central nervous system (CNS) of mice by Cre/LoxP system and generated the PP2ACα deficient mice (designated as the P p2 acα −/− mice). PP2ACα deletion results in DNA damage in neuroprogenitor cells (NPCs), which impairs memory formation and cortical neurogenesis. We first identify that PP2ACα can directly associate with Ataxia telangiectasia mutant kinase (ATM) and Ataxia telangiectasia/Rad3-related kinase (ATR) in neocortex and NPCs. Importantly, the P53 and hypermethylated in cancer 1 (HIC1) function complex, the newly found down-stream executor of the ATR/ATM cascade, will be translocated into nuclei and interact with homeodomain interacting protein kinase 2 (HIPK2) to respond to DNA damage. Notably, HICI plays a direct transcriptional regulatory role in HIPK2 gene expression. The interplay among P53, HIC1 and HIPK2 maintains DNA stability in neuroprogenitor cells. Taken together, our findings highlight a new role of PP2ACα in regulating early neurogenesis through maintaining DNA stability in neuroprogenitor cells. The P53/HIC/HIPK2 regulation loop, directly targeted by the ATR/ATM cascade, is involved in DNA repair in neuroprogenitor cells. [ABSTRACT FROM AUTHOR]

Digestive system cancers account for nearly half of all cancers around the world and have a high mortality rate. Cell culture and animal models represent cornerstones of digestive cancer research. However, their ability to enable cancer precision medicine is limited. Cell culture models cannot retain the genetic and phenotypic heterogeneity of tumors and lack tumor microenvironment (TME). Patient-derived xenograft mouse models are not suitable for immune-oncology research. While humanized mouse models are time- and cost-consuming. Suitable preclinical models, which can facilitate the understanding of mechanisms of tumor progression and develop new therapeutic strategies, are in high demand. This review article summarizes the recent progress on the establishment of TME by using tumor organoid models and microfluidic systems. The main challenges regarding the translation of organoid models from bench to bedside are discussed. The integration of organoids and a microfluidic platform is the emerging trend in drug screening and precision medicine. A future prospective on this field is also provided. [ABSTRACT FROM AUTHOR]

Abstract: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play significant roles in vertebrate organogenesis and morphogenesis. FGFR3 is a negative regulator of chondrogenesis and multiple mutations with constitutive activity of FGFR3 result in achondroplasia, one of the most common dwarfisms in humans, but the molecular mechanism remains elusive. In this study, we found that chondrocyte-specific deletion of BMP type I receptor a (Bmpr1a) rescued the bone overgrowth phenotype observed in Fgfr3 deficient mice by reducing chondrocyte differentiation. Consistently, using in vitro chondrogenic differentiation assay system, we demonstrated that FGFR3 inhibited BMPR1a-mediated chondrogenic differentiation. Furthermore, we showed that FGFR3 hyper-activation resulted in impaired BMP signaling in chondrocytes of mouse growth plates. We also found that FGFR3 inhibited BMP-2- or constitutively activated BMPR1-induced phosphorylation of Smads through a mechanism independent of its tyrosine kinase activity. We found that FGFR3 facilitates BMPR1a to degradation through Smurf1-mediated ubiquitination pathway. We demonstrated that down-regulation of BMP signaling by BMPR1 inhibitor dorsomorphin led to the retardation of chondrogenic differentiation, which mimics the effect of FGF-2 on chondrocytes and BMP-2 treatment partially rescued the retarded growth of cultured bone rudiments from thanatophoric dysplasia type II mice. Our findings reveal that FGFR3 promotes the degradation of BMPR1a, which plays an important role in the pathogenesis of FGFR3-related skeletal dysplasia. [Copyright &y& Elsevier]

Summary: DNA damage elicits a cellular signaling response that initiates cell cycle arrest and DNA repair. Here, we find that DNA damage triggers a critical block in glutamine metabolism, which is required for proper DNA damage responses. This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into tricarboxylic acid cycle. SIRT4 loss leads to both increased glutamine-dependent proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes. Moreover, SIRT4 knockout mice spontaneously develop lung tumors. Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest, and tumor suppression. [Copyright &y& Elsevier]

Summary: Members of sirtuin family regulate multiple critical biological processes, yet their role in carcinogenesis remains controversial. To investigate the physiological functions of SIRT2 in development and tumorigenesis, we disrupted Sirt2 in mice. We demonstrated that SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its coactivators, APCCDH1 and CDC20. SIRT2 deficiency caused increased levels of mitotic regulators, including Aurora-A and -B that direct centrosome amplification, aneuploidy, and mitotic cell death. Sirt2-deficient mice develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing more hepatocellular carcinoma (HCC). Human breast cancers and HCC samples exhibited reduced SIRT2 levels compared with normal tissues. These data demonstrate that SIRT2 is a tumor suppressor through its role in regulating mitosis and genome integrity. [ABSTRACT FROM AUTHOR]

Summary: The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3−/− mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3−/− MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3−/− MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3−/− mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor. [Copyright &y& Elsevier]

Summary: In lower eukaryotes, Sir2 serves as a histone deacetylase and is implicated in chromatin silencing, longevity, and genome stability. Here we mutated the Sirt1 gene, a homolog of yeast Sir2, in mice to study its function. We show that a majority of SIRT1 null embryos die between E9.5 and E14.5, displaying altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage. We demonstrate that Sirt1+/−;p53+/− mice develop tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduces tumorigenesis. Finally, we show that many human cancers exhibit reduced levels of SIRT1 compared to normal controls. Thus, SIRT1 may act as a tumor suppressor through its role in DNA damage response and genome integrity. [Copyright &y& Elsevier]

Background: Although substantial evidence supports the view that adult neurogenesis is involved in learning and memory, how newly generated neurons contribute to the cognitive process remains unknown. Fibroblast growth factor 2 (FGF-2) is known to stimulate the proliferation of neuronal progenitor cells (NPCs) in adult brain. Using conditional knockout mice that lack brain expression of FGFR1, a major receptor for FGF-2, we have investigated the role of adult neurogenesis in hippocampal synaptic plasticity and learning and memory. Methods: The Fgfr1 conditional knockout mice were generated by crossing the Fgfr1-null line, the Fgfr1-flox line, and the Nestin-Cre transgenic mice. Bromodeoxyuridine (BrdU) labeling, slice electrophysiology, and Morris Water Maze experiments were performed with the Fgfr1 conditional mutant mice. Results: Bromodeoxyuridine labeling experiments demonstrate that FGFR1 is required for the proliferation of NPCs as well as generation of new neurons in the adult dentate gyrus (DG). Moreover, deficits in neurogenesis in Fgfr1 mutant mice are accompanied by a severe impairment of long-term potentiation (LTP) at the medial perforant path (MPP)-granule neuron synapses in the hippocampal dentate. Moreover, the Fgfr1 mutant mice exhibit significant deficits in memory consolidation but not spatial learning. Conclusions: Our study suggests a critical role of FGFR1 in adult neurogenesis in vivo, provides a potential link between proliferative neurogenesis and dentate LTP, and raises the possibility that adult neurogenesis might contribute to memory consolidation. [Copyright &y& Elsevier]

Summary: Periodic formation of somites is controlled by the segmentation clock, where the oscillator Hes7 regulates cyclic expression of the Notch modulator Lunatic fringe. Here, we show that Hes7 also regulates cyclic expression of the Fgf signaling inhibitor Dusp4 and links Notch and Fgf oscillations in phase. Strikingly, inactivation of Notch signaling abolishes the propagation but allows the initiation of Hes7 oscillation. By contrast, transient inactivation of Fgf signaling abolishes the initiation, whereas sustained inactivation abolishes both the initiation and propagation of Hes7 oscillation. We thus propose that Hes7 oscillation is initiated by Fgf signaling and propagated/maintained anteriorly by Notch signaling. [Copyright &y& Elsevier]

Summary: Oncogenic Kras initiates pancreatic tumorigenesis, while subsequent genetic events shape the resultant disease. We show here that concomitant expression of KrasG12D and haploinsufficiency of the Smad4/Dpc4 tumor suppressor gene engenders a distinct class of pancreatic tumors, mucinous cystic neoplasms (MCNs), which culminate in invasive ductal adenocarcinomas. Disease evolves along a progression scheme analogous to, but distinct from, the classical PanIN-to-ductal adenocarcinoma sequence, and also portends a markedly different prognosis. Progression of MCNs is accompanied by LOH of Dpc4 and mutation of either p53 or p16. Thus, these distinct phenotypic routes to invasive adenocarcinoma nevertheless share the same overall mutational spectra. Our findings suggest that the sequence, as well as the context, in which these critical mutations are acquired helps determine the ensuing pathology. [Copyright &y& Elsevier]

Until recently, little was known about the possible physiological functions of the M5 muscarinic acetylcholine receptor subtype, the last member of the muscarinic receptor family (M1–M5) to be cloned. To learn more about the potential physiological roles of this receptor subtype, we generated and analyzed M5 receptor-deficient mice (M5 -/- mice). Strikingly, acetylcholine, a potent dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5 -/- mice, suggesting that endothelial M5 receptors mediate this activity in wild-type mice. This effect was specific for cerebral blood vessels, since acetylcholine-mediated dilation of extra-cerebral arteries remained fully intact in M5 -/- mice. In addition, in vitro neurotransmitter release experiments indicated that M5 receptors located on dopaminergic nerve terminals play a role in facilitating muscarinic agonist-induced dopamine release in the striatum, consistent with the observation that the dopaminergic neurons innervating the striatum almost exclusively express the M5 receptor subtype. We also found that the rewarding effects of morphine, the prototypical opiate analgesic, were substantially reduced in M5 -/- mice, as measured in the conditioned place preference paradigm. Furthermore, both the somatic and affective components of naloxone-induced morphine withdrawal symptoms were significantly attenuated in M5 -/- mice. It is likely that these behavioral deficits are caused by the lack of mesolimbic M5 receptors, activation of which is known to stimulate dopamine release in the nucleus accumbens. These results convincingly demonstrate that the M5 muscarinic receptor is involved in modulating several important pharmacological and behavioral functions. These findings may lead to novel therapeutic strategies for the treatment of drug addiction and certain cerebrovascular disorders. [Copyright &y& Elsevier]

Apert syndrome (AS) is one of the most severe craniosynostoses and is characterized by premature fusion of craniofacial sutures. Mutations of either Ser252Trp or Pro253Arg in fibroblast growth factor receptor 2 (FGFR2) are responsible for nearly all known cases of AS. Here we show that mutant mice carrying the activation mutation, Ser250Trp, which corresponds to Ser252Trp in human FGFR2, have malformations mimicking the skull abnormalities found in AS patients. Mutant mice (Fgfr2250/+) are smaller in body size with brachycephaly and exhibit distorted skulls with widely spaced eyes. Unexpectedly, the premature closure of the coronal suture is accompanied by decreased, rather than increased, bone formation. We demonstrate that the Fgfr2-Ser250Trp mutation does not cause obvious alterations in cell proliferation and differentiation; however, it results in increased Bax expression and apoptosis of osteogenic cells in mutant coronal suture. The accelerated cell death possibly reduces the space between osteogenic fronts of flat bones and results in the physical contact of these bones. Thus, our data reveal that dysregulated apoptosis plays an important role in the pathogenesis of AS related phenotypes. [Copyright &y& Elsevier]

Retraction notice to "PP2AC deficiency impairs early cortical development through inducing DNA damage in neuroprojenitor cells" [Int. J. Biochem. The University of Macau states that Bo Liu is not affiliated with the University of Macau. Lin Lin confirmed the affiliation with The University of California Riverside; Chu-Xia Deng confirmed the affiliation with the University of Macau; Wei-Min Tong confirmed the affiliation with the Chinese Academy of Medical Sciences. [Extracted from the article]