117 research outputs found
Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope
Cyclin-dependent kinases (CDKs) play key roles in cell cycle regulation. Genetic analysis in mice has revealed an essential role for Cdk2 in meiosis, which renders Cdk2 knockout (KO) mice sterile. Here we show that mice deficient in RingoA, an atypical activator of Cdk1 and Cdk2 that has no amino acid sequence homology to cyclins, are sterile and display meiotic defects virtually identical to those observed in Cdk2 KO mice including non-homologous chromosome pairing, unrepaired double-strand breaks, undetectable sex-body and pachytene arrest. Interestingly, RingoA is required for Cdk2 targeting to telomeres and RingoA KO spermatocytes display severely affected telomere tethering as well as impaired distribution of Sun1, a protein essential for the attachment of telomeres to the nuclear envelope. Our results identify RingoA as an important activator of Cdk2 at meiotic telomeres, and provide genetic evidence for a physiological function of mammalian Cdk2 that is not dependent on cyclins
Mathematical models for somite formation
Somitogenesis is the process of division of the anterior–posterior vertebrate embryonic axis into similar morphological units known as somites. These segments generate the prepattern which guides formation of the vertebrae, ribs and other associated features of the body trunk. In this work, we review and discuss a series of mathematical models which account for different stages of somite formation. We begin by presenting current experimental information and mechanisms explaining somite formation, highlighting features which will be included in the models. For each model we outline the mathematical basis, show results of numerical simulations, discuss their successes and shortcomings and avenues for future exploration. We conclude with a brief discussion of the state of modeling in the field and current challenges which need to be overcome in order to further our understanding in this area
Mathematical models for somite formation
Somitogenesis is the process of division of the anterior–posterior vertebrate embryonic axis into similar morphological units known as somites. These segments generate the prepattern which guides formation of the vertebrae, ribs and other associated features of the body trunk. In this work, we review and discuss a series of mathematical models which account for different stages of somite formation. We begin by presenting current experimental information and mechanisms explaining somite formation, highlighting features which will be included in the models. For each model we outline the mathematical basis, show results of numerical simulations, discuss their successes and shortcomings and avenues for future exploration. We conclude with a brief discussion of the state of modeling in the field and current challenges which need to be overcome in order to further our understanding in this area
Dkk1 and noggin cooperate in mammalian head induction
Growth factor antagonists play important roles in mediating the inductive effects of the Spemann organizer in amphibian embryos and its equivalents in other vertebrates. Dual inhibition of Wnt and BMP signals has been proposed to confer head organizer activity. We tested the requirement of this coinhibition in Xenopus and mice. In Xenopus, simultaneous reduction of the BMP antagonists chordin and noggin, and the Wnt antagonist dickkopf1 (dkk1) leads to anterior truncations. In mice, compound mutants for dkk1 and noggin display severe head defects, with deletion of all head structures anterior to the mid-hindbrain boundary. These defects arise as a result of a failure in anterior specification at the gastrula stage. The results provide genetic evidence for the dual inhibition model and indicate that dkk1 and noggin functionally cooperate in the head organizer
Genetic analysis of specific and redundant roles for p38 alpha and p38 beta MAPKs during mouse development
p38 alpha MAPK is an important regulator of cellular responses induced by external cues, but the elucidation of physiological functions for p38 alpha has been complicated by the possible functional redundancy in vivo with the related family member p38 beta. We found that mice with combined deletion of p38 alpha and p38 beta display diverse developmental defects at midgestation, including major cardiovascular abnormalities, which are observed neither in single knockout nor in double heterozygous embryos. Expression analysis indicates specific functions of p38 alpha and p38 beta in the regulation of cardiac gene expression during development. By using knock-in animals that express p38 beta under control of the endogenous p38 alpha promoter, we also found that p38 beta cannot perform all of the functions of p38 alpha during embryogenesis. Our results identify essential roles for p38 alpha and p38 beta during development and suggest that some specific functions may be explained by differences in expression patterns.</p
neurogenin1 Is Essential for the Determination of Neuronal Precursors for Proximal Cranial Sensory Ganglia
The NEUROGENINS (NGNs) are neural-specific basic helix–loop–helix (bHLH) transcription factors. Mouse embryos lacking ngn1 fail to generate the proximal subset of cranial sensory neurons. ngn1 is required for the activation of a cascade of downstream bHLH factors, including NeuroD, MATH3, and NSCL1. ngn1 is expressed by placodal ectodermal cells and acts prior to neuroblast delamination. Moreover, NGN1 positively regulates the Delta homolog DLL1 and can be negatively regulated by Notch signaling. Thus, ngn1 functions similarly to the proneural genes in Drosophila. However, the initial pattern of ngn1 expression appears to be Notch independent. Taken together with the fact that ectopic ngn1 expression can convert ectodermal cells to neurons in Xenopus ( Ma et al. 1996), these data and those of Fode et al. 1998) identify ngns as vertebrate neuronal determination genes, analogous to myoD and myf5 in myogenesis
The zebrafish Hairy/Enhancer-of-split-related gene her6 is segmentally expressed during the early development of hindbrain and somites
The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
Accurate DNA replication is crucial for the maintenance of genome integrity. To this aim, cells have evolved complex surveillance mechanisms to prevent mitotic entry in the presence of partially replicated DNA. ATR and Chk1 are key elements in the signal transduction pathways of DNA replication checkpoint; however, other kinases also make significant contributions. We show here that the stress kinases p38 and JNK are activated when DNA replication is blocked, and that their activity allows S/M, but not G₂/M, checkpoint maintenance when Chk1 is inhibited. Activation of both kinases by DNA replication inhibition is not mediated by the caffeine-sensitive kinases ATR or ATM. Phosphorylation of MKK3/6 and MKK4, p38 and JNK upstream kinases was also observed upon DNA replication inhibition. Using a genetic approach, we dissected the p38 pathway and showed that both p38α and p38β isoforms collaborate to inhibit mitotic entry. We further defined MKK3/6 and MK2/3 as the key upstream and downstream elements in the p38 signaling cascade after replication arrest. Accordingly, we found that the stress signaling pathways collaborate with Chk1 to keep cyclin B1/Cdk1 complexes inactive when DNA replication is inhibited, there by preventing cell cycle progression when DNA replication is stalled. Our results show a complex response to replication stress, where multiple pathways are activated and fulfill overlapping roles to prevent mitotic entry with unreplicated DNA
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