| Abstract No.: | A-A1008 |
| Country: | Canada |
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| Title: | A ROLE FOR ACTIVATED H-RAS IN CORTICAL DEVELOPMENT AND COSTELLO SYNDROME |
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| Authors/Affiliations: | 1 Annie Paquin*; 1 Christian Hordo; 1 David R. Kaplan; 1 Freda D. Miller;
1 Hospital for Sick Children - University of Toronto, ON, Canada
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| Content: | Introduction: Development of the mammalian cerebral cortex is a sequentially timed process whereby neurons followed by glial cells develop from a single layer of neuroepithelial cortical precursor cells. This timed cell genesis has been shown to be under the control of both intrinsic mechanisms and environmental cues. In this regard, genetic mutations resulting in constitutive activation of H-Ras cause Costello Syndrome (CS), a complex developmental disorder associated with failure to thrive and profound mental retardation.
Objective: We have asked whether this mental retardation might be a consequence of aberrant neural precursor cell proliferation and/or differentiation.
Materials and methods: We have used two H-Ras mutations present in CS patients, H-RasV12 (G12V) and H-RasG12S, and have studied their effects on proliferation, survival, and differentiation of embryonic cortical precursor cells in culture and in vivo. RESULTS: Theses studies show that both of these mutants inhibit neurogenesis and promote the formation of astrocytes in primary cell cultures. Furthermore, clonal analysis demonstrates that this increase in astrogenesis is at the expense of neurogenesis. In utero electroporation of these mutants into cortical precursors in vivo indicate that expression of either form of constitutively activated H-Ras promotes cell proliferation and inhibits neurogenesis. Moreover, these H-Ras mutants promoted premature gliogenesis, causing formation of astrocytes at a time when normal gliogenesis has not yet started. CONCLUSION: Aberrant H-Ras activation enhances neural precursor cell proliferation, and perturbs the normal genesis of neurons and glial cells, effects that likely contribute to the cognitive dysfunction seen in Costello Syndrome. |
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