Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly

被引:106
作者
Chen, Lei
Liao, Guanghong
Yang, Linda
Campbell, Kenneth
Nakafuku, Masato
Kuan, Chia-Yi
Zheng, Yi
机构
[1] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol, Cincinnati, OH 45229 USA
[2] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA
[3] Univ Cincinnati, Coll Med, Mol & Dev Biol Grad Program, Cincinnati, OH 45229 USA
关键词
neurogenesis; polarity; radial glia;
D O I
10.1073/pnas.0603533103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:16520 / 16525
页数:6
相关论文
共 31 条
[1]  
Anderson RM, 2002, DEVELOPMENT, V129, P4975
[2]   The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface [J].
Cappello, Silvia ;
Attardo, Alessio ;
Wu, Xunwei ;
Iwasato, Takuji ;
Itohara, Shigeyoshi ;
Wilsch-Braeuninger, Michaela ;
Eilken, Hanna M. ;
Rieger, Michael A. ;
Schroeder, Timm T. ;
Huttner, Wieland B. ;
Brakebusch, Cord ;
Goetz, Magdalena .
NATURE NEUROSCIENCE, 2006, 9 (09) :1099-1107
[3]   The hyh mutation uncovers roles for αSnap in apical protein localization and control of neural cell fate [J].
Chae, TH ;
Kim, S ;
Marz, KE ;
Hanson, PI ;
Walsh, CA .
NATURE GENETICS, 2004, 36 (03) :264-270
[4]   Cdc42 is required for PIP2-induced actin polymerization and early development but not for cell viability [J].
Chen, F ;
Ma, L ;
Parrini, MC ;
Mao, X ;
Lopez, M ;
Wu, C ;
Marks, PW ;
Davidson, L ;
Kwiatkowski, DJ ;
Kirchhausen, T ;
Orkin, SH ;
Rosen, FS ;
Mayer, BJ ;
Kirschner, MW ;
Alt, FW .
CURRENT BIOLOGY, 2000, 10 (13) :758-765
[5]   Central roles of the roof plate in telencephalic development and holoprosencephaly [J].
Cheng, Xun ;
Hsu, Ching-mei ;
Currle, D. Spencer ;
Hu, Jia Sheng ;
Barkovich, A. James ;
Monuki, Edwin S. .
JOURNAL OF NEUROSCIENCE, 2006, 26 (29) :7640-7649
[6]   Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function [J].
Chiang, C ;
Ying, LTT ;
Lee, E ;
Young, KE ;
Corden, JL ;
Westphal, H ;
Beachy, PA .
NATURE, 1996, 383 (6599) :407-413
[7]   EMBRYONIC BRAIN ENLARGEMENT REQUIRES CEREBROSPINAL-FLUID PRESSURE [J].
DESMOND, ME ;
JACOBSON, AG .
DEVELOPMENTAL BIOLOGY, 1977, 57 (01) :188-198
[8]   Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCζ [J].
Etienne-Manneville, S ;
Hall, A .
CELL, 2001, 106 (04) :489-498
[9]   Rho-family GTPases in cadherin-mediated cell-cell adhesion [J].
Fukata, M ;
Kaibuchi, K .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2001, 2 (12) :887-897
[10]   Ectopic bone morphogenetic proteins 5 and 4 in the chicken forebrain lead to cyclopia and holoprosencephaly [J].
Golden, JA ;
Bracilovic, A ;
McFadden, KA ;
Beesley, JS ;
Rubenstein, JLR ;
Grinspan, JB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (05) :2439-2444