Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly
- Lei Chen*,†,
- Guanghong Liao‡,
- Linda Yang*,†,
- Kenneth Campbell†,‡,
- Masato Nakafuku†,‡,
- Chia-Yi Kuan†,‡,§, and
- Yi Zheng*,†,§
- *Divisions of Experimental Hematology and
- ‡Developmental Biology, Cincinnati Children's Hospital Medical Center and
- †Molecular and Developmental Biology Graduate Program, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229
-
Edited by Pasko Rakic, Yale University School of Medicine, New Haven, CT, and approved September 13, 2006 (received for review May 1, 2006)
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 apical/ventricular surface and the ascending of radial glia/progenitor fibers toward the pial/basal 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 gene-targeting 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, β-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 apical-basal polarity of the telencephalic NE, which is needed for the expansion and bifurcation of cerebral hemispheres.
Footnotes
- §To whom correspondence may be addressed. E-mail: alex.kuan{at}chmcc.org or yi.zheng{at}chmcc.org
-
Author contributions: L.C., C.-Y.K., and Y.Z. designed research; L.C., G.L., and C.-Y.K. performed research; L.C., L.Y., K.C., M.N., C.-Y.K., and Y.Z. contributed new reagents/analytic tools; L.C., C.-Y.K., and Y.Z. analyzed data; and L.C., C.-Y.K., and Y.Z. wrote the paper.
-
The authors declare no conflict of interest.
-
This article is a PNAS direct submission.
- Abbreviations:
- NE,
- neuroepithelium;
- Shh,
- Sonic hedgehog.
- © 2006 by The National Academy of Sciences of the USA
