Mutations in the Notch Pathway Alter the Patterning of Multifidus

Clinical studies have suggested that defects in the epaxial muscles, particularly multifidus, may contribute to the etiology of idiopathic scoliosis. While the epaxial muscles and the vertebrae derive from the same embryonic segmentation process, the mechanisms that pattern the multisegmental back muscles are still unclear. The process of segmentation is regulated by the Notch signaling pathway, and mutations in the modulators delta‐like 3 (Dll3) and lunatic fringe (Lfng) are genetic models for spinal disorders such as scoliosis. Osteological defects have been characterized in these genetic models, but myological phenotypes have not previously been studied. We analyzed the multifidus muscle in the mouse (Mus musculus) and observed intriguing changes in the cranio‐caudal borders of multifidus in Dll3 and Lfng models. Statistical analysis did not find a significant association between the majority of the multifidus anomalies and the vertebral defects, suggesting a previously unappreciated role for Notch signaling in patterning epaxial muscle groups. These findings indicate an additional mechanism by which DLL3 and LFNG may play a role in the etiology of human idiopathic scoliosis. Anat Rec, 2012. © 2011 Wiley Periodicals, Inc.     

Differential activity of Wnt/β‐catenin signaling in the embryonic mouse thalamus

In neural development, several Wnt genes are expressed in the vertebrate diencephalon, including the thalamus. However, roles of Wnt signaling in the thalamus during neurogenesis are not well understood. We examined Wnt/β‐catenin activity in embryonic mouse thalamus and found that a Wnt target gene Axin2 and reporter activity of BAT‐gal transgenic mice show similar, differential patterns within the thalamic ventricular zone, where ventral and rostral regions had lower activity than other regions. Expression of Wnt ligands and signaling components also showed complex, differential patterns. Finally, based on partially reciprocal patterns of Wnt and Shh signals in the thalamic ventricular zone, we tested if Shh signal is sufficient or necessary for the differential Axin2 expression. Analysis of mice with enhanced or reduced Shh signal showed that Axin2 expression is similar to controls. These results suggest that differential Wnt signaling may play a role in patterning the thalamus independent of Shh signaling. Developmental Dynamics 238:3297–3309, 2009. © 2009 Wiley‐Liss, Inc.     

her9 promotes floor plate development in zebrafish.

Notochord, floor plate, and in anamniotes hypochord, are vertebrate embryonic midline structures that are the sources of molecules that pattern the nervous system, somites, and dorsal aorta. Midline precursor cells arise from the dorsal organizer during gastrulation, and Notch signaling is an important regulator of midline cell fate specification. To understand fully how Notch signaling regulates midline development, we investigated the role of potential Notch target genes. We show here that midline precursors express her9, a member of the hairy/Enhancer of split gene family. Although her9 inhibits notochord development and promotes floor plate specification, her9 expression in floor plate cells appears not to require Notch signaling. We show that, instead, her9 is a downstream effector of Nodal signaling for floor plate specification.     

Transcriptional oscillation of lunatic fringe is essential for somitogenesis

A molecular oscillator that controls the expression of cyclic genes such as lunatic fringe (Lfng) in the presomitic mesoderm has been shown to be coupled with somite formation in vertebrate embryos. To address the functional significance of oscillating Lfng expression, we have generated transgenic mice expressing Lfng constitutively in the presomitic mesoderm in addition to the intrinsic cyclic Lfng activity. These transgenic lines displayed defects of somite patterning and vertebral organization that were very similar to those of Lfng null mutants. Furthermore, constitutive expression of exogenous Lfng did not compensate for the complete loss of cyclic endogenous Lfng activity. Noncyclic exogenous Lfng expression did not abolish cyclic expression of endogenous Lfng in the posterior presomitic mesoderm (psm) but affected its expression pattern in the anterior psm. Similarly, dynamic expression of Hes7 was not abolished but abnormal expression patterns were obtained. Our data are consistent with a model in which alternations of Lfng activity between ON and OFF states in the presomitic mesoderm prior to somite segmentation are critical for proper somite patterning, and suggest that Notch signaling might not be the only determinant of cyclic gene expression in the presomitic mesoderm of mouse embryos.     

lunatic fringe regulates Delta-Notch induction of hypochord in zebrafish.

Cells that occupy the midline of vertebrate embryos arise from a common population of precursors. Several lines of evidence indicate that Delta-Notch signaling regulates specification of midline precursors for different fates. We show that zebrafish midline precursors transiently express lunatic fringe, which encodes a glycosyltransferase that modifies Notch activity in response to its ligands, and that lunatic fringe function is required for Delta-Notch-mediated induction of hypochord cells at the lateral borders of the midline precursor domain.     

Notch信号通路与心血管发育的关系

Notch信号通路在脊椎动物和无脊椎动物中高度保守,它在决定细胞的分化上起重要作用。Notch信号通路由受体、配体和核效应物三部分组成。它对正常心血管系统的发育有重要作用,Notch信号表达不足或者过量都会造成动物因心血管异常而死亡。正常情况下,Notch信号抑制胚胎干细胞向心肌细胞的分化。此外,Notch信号在动静脉分化中也具有重要作用,它能促进前体细胞向动脉细胞发育。     

Valproic acid,a histone deacetylase inhibitor,regulates cell proliferation in the adult zebrafish optic tectum

Background: Valproic acid (VPA) has been used to treat epilepsy and bipolar disorder. Several reports have demonstrated that VPA functions as a histone deacetylase (HDAC) inhibitor. While VPA is known to cause teratogenic changes in the embryonic zebrafish brain, its effects on neural stem cells (NSCs) in both the embryonic and adult zebrafish are not well understood. Results: In this study, we observed a proliferative effect of VPA on NSCs in the embryonic hindbrain. In contrast, VPA reduced cell proliferation in the adult zebrafish optic tectum. Treatment with HDAC inhibitors showed a similar inhibitory effect on cell proliferation in the adult zebrafish optic tectum, suggesting that VPA reduces cell proliferation through HDAC inhibition. Cell cycle progression was also suppressed in the optic tectum of the adult zebrafish brain because of HDAC inhibition. Recent studies have demonstrated that HDAC inhibits the Notch signaling pathway; hence, adult zebrafish were treated with a Notch inhibitor. This increased the number of proliferating cells in the adult zebrafish optic tectum with down‐regulated expression of her4, a target of Notch signaling. Conclusions: These results suggest that VPA inhibits HDAC activity and upregulates Notch signaling to reduce cell proliferation in the optic tectum of adult zebrafish. Developmental Dynamics 243:1401–1415, 2014. © 2014 Wiley Periodicals, Inc.     

Xenopus Rnd1 and Rnd3 GTP‐binding proteins are expressed under the control of segmentation clock and required for somite formation

The process of segmentation in vertebrates is described by a clock and wavefront model consisting of a Notch signal and an fibroblast growth factor‐8 (FGF8) gradient, respectively. To further investigate the segmentation process, we screened gene expression profiles for downstream targets of the segmentation clock. The Rnd1 and Rnd3 GTP‐binding proteins comprise a subgroup of the Rho GTPase family that show a specific expression pattern similar to the Notch signal component ESR5, suggesting an association between Rnd1/3 and the segmentation clock. Rnd1/3 expression patterns are disrupted by overexpression of dominant‐negative or active forms of Notch signaling genes, and responds to the FGF inhibitor SU5402 by a posterior shift analogous to other segmentation‐related genes, suggesting that Rnd1/3 expressions are regulated by the segmentation clock machinery. We also show that antisense morpholino oligonucleotides to Rnd1/3 inhibit somite segmentation and differentiation in Xenopus embryos. These results suggest that Rnd1/3 are required for Xenopus somitogenesis. Developmental Dynamics 238:2867–2876, 2009. © 2009 Wiley‐Liss, Inc.     

Chicken dapper genes are versatile markers for mesodermal tissues,embryonic muscle stem cells,neural crest cells,and neurogenic placodes

Dapper (Dpr) proteins are context‐dependent regulators of Wnt and Tgfβ signaling. However, although inroads into their molecular properties have been made, their expression and biological function are not understood. Searching for avian Dpr genes, we found that the chicken harbors a Dpr1 and a Dpr2 paralogue only. The genes are expressed in distinct patterns at gastrulation, neurulation, and organogenesis stages of development with key expression domains being the posterior primitive streak, anterior node and notochord, presomitic mesoderm (segmental plate), lateral and cardiac mesoderm, limb mesenchyme, and neurogenic placodes for Dpr1, and anterior primitive streak, node, epithelial somites, embryonic muscle stem cells, oral ectoderm and endoderm, neural crest cells, limb ectoderm, and lung buds for Dpr2. Expression overlaps in a few tissues; however, in several tissues, expression is complementary. Developmental Dynamics 238:1166–1178, 2009. © 2009 Wiley‐Liss, Inc.     

Serum and glucocorticoid‐inducible kinase 1 (SGK1) is necessary for vascular remodeling during angiogenesis

The unquestionable importance of the cardiovascular system for pre‐ and postnatal life has prompted dissection of the molecular mechanisms underlying its development. Serum and glucocorticoid‐inducible kinase 1 (SGK1) is a serine/threonine kinase lying downstream of the phosphoinositide 3 (PI3) kinase pathway, whose embryonic function remains unknown. Here, we show that disruption of Sgk1 in the mouse C57BL/6J genetic background leads to embryonic lethality at embryonic day 10.5–11.5 due to severe embryonic and extraembryonic angiogenic defects and to impaired myocardial trabeculation. Absence of SGK1 results in increased apoptosis of endothelial cells, and of vascular smooth muscle cells highlighting a prosurvival role for SGK1 during angiogenesis. Sgk1 null embryos also display reduced expression levels of Notch signaling genes and decreased expression of the arterial markers Efnb2 and Nrp1. These findings uncover a novel and essential function for SGK1 in cardiovascular development contributing to a better understanding of mammalian angiogenesis. Developmental Dynamics 239:2149–2160, 2010. © 2010 Wiley‐Liss, Inc.