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Loss of Dvl1 and 3 Induces Early Brain Overgrowth Via Transcriptional Deregulation of Beta-Catenin, Brn2 and Tbr2

Thursday, 2 May 2013: 09:00-13:00
Banquet Hall (Kursaal Centre)
H. Belinson1, J. Nakatani1, R. Y. Birnbaum2, N. Ahituv2, R. J. McEvilly3, M. G. Rosenfeld3 and A. Wynshaw-Boris1, (1)Department of Pediatrics, Institute for Human Genetics, UCSF, San Francisco, CA, (2)Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, UCSF, San Francisco, CA, (3)San Diego School of Medicine, UCSD, San Diego, CA
Background:  The development and growth of the brain is regulated by the highly conserved wingless/Wnt signaling pathway. The Dishevelled (Dvl) family of proteins, consisting of Dvl1, Dvl2 and Dvl3 relay Wnt signals from receptors to downstream effectors. Wnt canonical downstream effector, β-Catenin, is a regulator of gene expression and cell fate specification. Previous studies of adult Dvl1-null mice revealed abnormal social interactions, without any gross pathological brain abnormalities.

Objectives:  We set out to test the hypothesis that additional reduction of Dvl allele may display pathological brain abnormalities during development.

Methods:  Dvl1-/-3+/-mice were generated and analyzed for early brain overgrowth, an established autistic phenotype.

Results: We found that Dvl1-/-3+/- mice display early embryonic brain overgrowth associated with induced proliferation and early expansion of cortical basal neural progenitors in vivo and in vitro. Induction of brain overgrowth was regulated by a cascade of transcriptional activity. β-catenin transcriptional activity was reduced in the Dvl1-/-3+/- neural progenitors which resulted in down-regulation of Brn2. Using Chromatin Immunoprecipitation (ChIP), we showed that Brn2 directly binds to and inhibits the expression of the basal transcription factor Tbr2. Thus in Dvl1-/-3+/-mice reduced Brn2 expression gave rise to Tbr2 upregulation, which consequently induced proliferation of the basal progenitor cells and their neuronal progeny in the cerebral cortex. Dvl mutant phenotype could be rescued using both genetic and pharmacological manipulations of Dvl downstream effectors.

Conclusions: Thus, we suggest that early brain overgrowth seen in Dvl1-/-3+/- mice is mediated by deregulation of the β-catenin/Brn2/Tbr2 transcriptional cascade, which may contribute to the social behavioral phenotype in the adult Dvl1-/-3+/- mice.

See more of: Animal Models of Autism
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