Stage-Specific Control of Neural Crest Stem Cell Proliferation by the Small Rho GTPases Cdc42 and Rac1

Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland.
Cell stem cell (Impact Factor: 22.27). 04/2009; 4(3):236-47. DOI: 10.1016/j.stem.2009.01.017
Source: PubMed


The neural crest (NC) generates a variety of neural and non-neural tissues during vertebrate development. Both migratory NC cells and their target structures contain cells with stem cell features. Here we show that these populations of neural crest-derived stem cells (NCSCs) are differentially regulated by small Rho GTPases. Deletion of either Cdc42 or Rac1 in the NC results in size reduction of multiple NC target structures because of increased cell-cycle exit, while NC cells emigrating from the neural tube are not affected. Consistently, Cdc42 or Rac1 inactivation reduces self-renewal and proliferation of later stage, but not early migratory NCSCs. This stage-specific requirement for small Rho GTPases is due to changes in NCSCs that, during development, acquire responsiveness to mitogenic EGF acting upstream of both Cdc42 and Rac1. Thus, our data reveal distinct mechanisms for growth control of NCSCs from different developmental stages.

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    • "Apoptosis, however, is cell-type specific, since Rac1 deletion in other cells types, e.g., keratinocytes in vivo does not cause apoptosis [8]. Neural crest cell-specific deletion of Rac1 did not affect cell migration, but it unexpectedly resulted in defective proliferation and selfrenewal at later stages leading to craniofacial and cardiac outflow tract defects [9] [10]. Melanocyte-specific Rac1 mutants showed less efficient melanoblast migration, and defective cell–cycle progression and cytokinesis [11], while in cerebellar granule neurons Rac1 was shown to be required for cell migration and axon formation via the WAVE complex [12]. "
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    • "BMP is thought to act by suppressing gliogenesis and by inducing ngn2 expression whereas FGF2 could prevent neurogenesis and promote gliogenesis by inhibiting ngn2 expression. Finally, an EGF/small-RhoGTPase signaling cascade as identified in the mouse (Fuchs et al., 2009), could regulate cell proliferation of DRG cells once they have reached their target. However, since the role of these factors and pathways is unknown in the axolotl, we first decided to characterize the proportion of neurons, glial cells, and their precursors during DRG size compensation. "
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    • "It is well known that many regulators including Rho-GTPases, PI3K, Par-complex are involved in the polarization process and regulate the actin cytoskeleton (Conde and Caceres 2009). It is unclear at the moment, which is the principal regulator of polarity but one hypothesis places Rac1 upstream of Cdc42 (Fuchs et al. 2009). However, it is likely that the exact mechanism of the regulation of polarity may be cell type specific (Etienne-Manneville and Hall 2003; Garvalov et al. 2007). "
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