Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly.
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, beta-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.
Chen
Lei
L
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Liao
Guanghong
G
Yang
Linda
L
Campbell
Kenneth
K
Nakafuku
Masato
M
Kuan
Chia-Yi
CY
Zheng
Yi
Y
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D016764:Cell Polarity; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D016142:Holoprosencephaly / Q000196:embryology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; C465570:Shh protein, mouse; D020764:cdc42 GTP-Binding Protein