Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly

Abstract

The telencephalic neuroepithelium (NE) of mammalian brain has an apical-basal polarity that is marked by the positioning of neural progenitors and adherens junctions on the apical͞ventricular surface and the ascending of radial glia͞progenitor fibers toward the pial͞basal surface. The signaling pathway that establishes this apical-basal polarity of NE is not completely understood, but the Rho-family GTPase Cdc42 may play a critical role because it controls cadherin-based intercellular junctions and cell polarity in many species. Here, we tested this hypothesis by a conditional genetargeting strategy by using the Foxg1-Cre line to delete Cdc42 in the telencephalic neural progenitors in mouse embryos. We found that Cdc42-deletion abolishes the apical localization of PAR6, aPKC, E-cadherin, ␤-catenin, and Numb proteins in the NE, and severely impairs the extension of nestin-positive radial fibers. Consequently, neural progenitors were scattered throughout the entire depth of the NE, and the Cdc42-deficient telencephalon failed to bulge or separate into two cerebral hemispheres, resulting in holoprosencephaly. However, neither the midline expression of Sonic hedgehog nor the dorso-ventral patterning of the telencephalon was affected by Cdc42-deletion. Taken together, these results indicate that Cdc42 has an essential role in establishing the apicalbasal polarity of the telencephalic NE, which is needed for the expansion and bifurcation of cerebral hemispheres.neurogenesis ͉ polarity ͉ radial glia

Loss of RhoA in neural progenitor cells causes the disruption of adherens junctions and hyperproliferation

“…Although Cdc42 deletions in previous reports also showed their essential roles in adherens junctions in the nervous system (14,15), there are also significant differences in the phenotypes of RhoA and Cdc42 deletions, even when the same Cre driver (i.e., Foxg1-Cre mice) was used. In Foxg1-Cdc42 null embryos, the disappearance of apical cadherin-catenin proteins started as early as E9.5-E10.5, causing holoprosencephaly due to failure to expand the telencephalon (15). In contrast, RhoA deletion by Foxg1-Cre or Wnt1-Cre drivers caused a gradual disruption of apical cadherin-catenin protein localization between E11.5 and E14.5.…”

“…The recent development of a conditional gene-targeting strategy has provided many new insights into the physiological functions of small Rho GTPases (13). For example, although Cdc42 and Rac1 are both implicated in epithelial apical junctions, conditional gene deletion in the telencephalon revealed that Cdc42, but not Rac1, is indispensable for the formation of apical adherens junctions in the developing brain (14)(15)(16). These findings underlie the importance of using conditional gene deletion to ascertain the biological functions of small Rho GTPases.…”

Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

“…Whether Cdc42 plays a role in HSC differentiation into various blood cell lineages will be an important question to address in future studies. Another aspect of this study is the implication that Cdc42 function in HSCs is unique, as Cdc42 is known for neuro-stem/ progenitor cell polarity establishment and for skin stem/ progenitor differentiation into the follicle lineage (28)(29)(30) and is required for supporting cell cycle progression through the G 1 /S phase, rather than maintaining cell cycle quiescence, in mouse embryonic fibroblasts (14,31). The findings further suggest an avenue for manipulating the HSC cell cycle status as well as the HSC-niche interaction in future therapeutic applications.…”

Interkinetic Nuclear Movement in the Ventricular Zone of the Cortex

“…The results of reduction in cellular polarity in the VZ are highly variable even with the same gene involved. For example, conditional knockout of cdc42 was carried out using different Cre drivers, in both cases reduced ventricular cell polarity was observed, followed by changes in cell fate (Chen et al 2006) or holoprosencephaly, a fusion of the two hemispheres (Chae et al 2004).…”