RhoA inhibits neural differentiation in murine stem cells through multiple mechanisms
| Autor: | Chuanshen Wu, Lars Jakobsson, Junning Yang, Inna Chervoneva, Arie Horowitz, Ioana Stefanescu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
rho GTP-Binding Proteins
0301 basic medicine animal structures RHOA Transcription Genetic rab3 GTP-Binding Proteins Cellular differentiation Embryoid body Biology Biochemistry Article Mice 03 medical and health sciences Animals Guanine Nucleotide Exchange Factors Noggin Molecular Biology Mice Knockout Neurons Cell Differentiation Mouse Embryonic Stem Cells Cell Biology Molecular biology Embryonic stem cell Cell biology Retinoic acid receptor 030104 developmental biology Bone morphogenetic protein 4 embryonic structures biology.protein Stem cell Carrier Proteins rhoA GTP-Binding Protein |
| Zdroj: | Science Signaling. 9 |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.aaf0791 |
| Popis: | Spontaneous neural differentiation of embryonic stem cells is induced by Noggin-mediated inhibition of bone morphogenetic protein 4 (BMP4) signaling. RhoA is a guanosine triphosphatase (GTPase) that regulates cytoskeletal dynamics and gene expression, both of which control stem cell fate. We found that disruption of Syx, a gene encoding a RhoA-specific guanine nucleotide exchange factor, accelerated retinoic acid-induced neural differentiation in murine embryonic stem cells aggregated into embryoid bodies. Cells from Syx(+/+) and Syx(-/-) embryoid bodies had different abundances of proteins implicated in stem cell pluripotency. The differentiation-promoting proteins Noggin and RARγ (a retinoic acid receptor) were more abundant in cells of Syx(-/-) embryoid bodies, whereas the differentiation-suppressing proteins SIRT1 (a protein deacetylase) and the phosphorylated form of SMAD1 (the active form of this transcription factor) were more abundant in cells of Syx(+/+) embryoid bodies. These differences were blocked by the overexpression of constitutively active RhoA, indicating that the abundance of these proteins was maintained, at least in part, by RhoA activity. The peripheral stress fibers in cells from Syx(-/-) embryoid bodies were thinner than those in Syx(+/+) cells. Furthermore, less Noggin and fewer vesicles containing Rab3d, a GTPase that mediates Noggin trafficking, were detected in cells from Syx(-/-) embryoid bodies, which could result from increased Noggin exocytosis. These results suggested that, in addition to inhibiting Noggin transcription, RhoA activity in wild-type murine embryonic stem cells also prevented neural differentiation by limiting Noggin secretion. |
| Databáze: | OpenAIRE |
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