The role of Cdc42 and Rac1 GTPases in mammalian forebrain development
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University of Cincinnati / OhioLINK
2006
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=ucin1163039225 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin11630392252021-08-03T06:11:26Z The role of Cdc42 and Rac1 GTPases in mammalian forebrain development Chen, Lei Rho GTPase forebrain development neuritogenesis axon guidance migration polarity patterning holoprosencephaly Rho family GTPases are key regulators of a variety of cell functions including actin cytoskeleton organization, gene transcription, cell cycle progression and vesicle trafficking. In the mammalian neuronal system the Rho family members Cdc42 and Rac1 have been suggested to play roles in neuronal morphogenesis and synaptic transmission in a body of literature that is derived by over-expression of dominant-negative or constitutive-active mutants in cell cultures or transgenic animals. To investigate the physiologic function of Cdc42 and Rac1 in mammalian neural development, we have applied a conditional gene targeting strategy by crossbreeding Foxg1-Cre gene targeted mice with Rac1 or Cdc42 gene floxed conditional strain to achieve the deletion of each gene specifically in the telencephalon. We found that Cdc42-deletion abolishes the polarity of neuroepithelial (NE) cells. 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. 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. In contrast to Cdc42 deletion, Rac1 deficiency in the forebrain does not affect the polarity of NE, but does cause a profound phenotype. The Rac1 deficient embryos exhibit defects in the midline commissural axon tract formation and the tangential migration of the olfactory and cortical interneurons. Unlike previous studies using dominant-negative mutants, deletion of Rac1 did not prevent axon outgrowth or radial migration of cortical projection neurons. Interestingly, the tangential migration was not affected by the ventral telencephalon SVZ-deletion of Rac1 in Dlx5/6-Cre/Rac1loxp/null mice. These results provide strong evidence that Rac1 is important in regulating axonal projection, but is dispensable for neuritogenesis per se. Furthermore, there appears a progenitor-specific requirement of Rac1 for the subsequent migration of ventral telencepahlon-derived interneurons. In summary, the collective results of the thesis studies suggest that Cdc42 and Rac1 have important but distinct roles during mammalian forebrain development. 2006 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1163039225 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1163039225 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Rho GTPase forebrain development neuritogenesis axon guidance migration polarity patterning holoprosencephaly |
| spellingShingle |
Rho GTPase forebrain development neuritogenesis axon guidance migration polarity patterning holoprosencephaly Chen, Lei The role of Cdc42 and Rac1 GTPases in mammalian forebrain development |
| author |
Chen, Lei |
| author_facet |
Chen, Lei |
| author_sort |
Chen, Lei |
| title |
The role of Cdc42 and Rac1 GTPases in mammalian forebrain development |
| title_short |
The role of Cdc42 and Rac1 GTPases in mammalian forebrain development |
| title_full |
The role of Cdc42 and Rac1 GTPases in mammalian forebrain development |
| title_fullStr |
The role of Cdc42 and Rac1 GTPases in mammalian forebrain development |
| title_full_unstemmed |
The role of Cdc42 and Rac1 GTPases in mammalian forebrain development |
| title_sort |
role of cdc42 and rac1 gtpases in mammalian forebrain development |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2006 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1163039225 |
| work_keys_str_mv |
AT chenlei theroleofcdc42andrac1gtpasesinmammalianforebraindevelopment AT chenlei roleofcdc42andrac1gtpasesinmammalianforebraindevelopment |
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