Activating mutations in fibroblast growth factor receptors (FGFR) -1, -2, -3 cause craniosynostosis, the premature fusion of one or more cranial sutures, in Apert, Crouzon, Pfeiffer, Muenke, and Beare-Stevenson cutis gyrata syndromes. These conditions are also characterized by other skeletal anomalies and variable effects on brain development and function. The variability of central nervous system defects and the occurrence of severe cognitive impairment despite early surgical intervention, particularly in Apert syndrome, led us to hypothesize that the activating FGFR mutations have a direct, adverse effect on brain development. In this study we looked for aberrations in diverse cellular processes affected by Fgf signaling in the developing telencephalon of an Fgfr2+/S252W Apert mouse model to uncover the mechanisms by which these defects occur. We present evidence that in the Apert mouse model, the radial glial cells to intermediate progenitor transition is depressed during mid-to-late neurogenesis. We also observed a significant increase in apoptosis in the anterior forebrain in Apert newborns. Lastly, an increase in the migration of astrocytes to the dorsolateral cortex by post-natal day five was observed. These results suggest that important physiological roles of Fgfr2 signaling in the development of the cerebral cortex are adversely affected by syndromic activating mutations of Fgfr2, which may lead to gross brain abnormalities.
|Advisor:||Jabs, Ethylin W.|
|Commitee:||Benson, Deanna L., Hof, Patrick R., Huntley, George W.|
|School:||Icahn School of Medicine at Mount Sinai|
|Department:||Genetics and Genomic Sciences|
|School Location:||United States -- New York|
|Source:||MAI 52/03M(E), Masters Abstracts International|
|Subjects:||Neurosciences, Genetics, Developmental biology|
|Keywords:||Apert syndrome, Cerebral cortex, Neurodevelopment|
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