Presentation Abstract

Program#/Poster#: 244.13/T9
Presentation Title: β-catenin transcriptionally regulates Brn2 and control early brain overgrowth
Location: Halls B-H
Presentation time: Sunday, Nov 10, 2013, 1:00 PM - 2:00 PM
Topic: ++C.07.a. Autism: Genetic and animal models
Authors: *H. BELINSON1, J. NAKATANI1, R. Y. BIRNBAUM2, M. BERSHTEYN1, B. BABINEAU1, R. J. MCEVILLY3, J. LONG1, K. WILLERT4, N. AHITUV2, M. G. ROSENFELD3, A. WYNSHAW-BORIS1,5;
1Pediatrics, 2Dept. of Bioengineering and Therapeut. Sci., Inst. For Human Genetics, UCSF, San Francisco, CA; 3Dept. and Sch. of Med., Howard Hughes Med. Institute, UCSD, San Diego, CA; 4Deparment of Cell and Mol. Biol., Inst. for Regenerative Medicine, UCSD, San Diego, CA; 5Dept. of Genet. and Genome Sci., Case Western Reserve Univ. Sch. of Med., Cleveland, OH
Abstract: Early brain overgrowth is a hallmark phenotype of autism, but the mechanisms linking regulation of brain size with social behavioral defects are unknown. The development of the neocortex is regulated by the highly conserved wingless/Wnt developmental pathway. A key component of Wnt pathway, the Dishevelled (Dvl) family of proteins, relays Wnt signals from receptors to downstream effectors. Dvl1-null mice exhibited abnormal social interaction however no gross brain pathological abnormalities were seen in these mice (Lijam et al., 1997; Long et al., 2004). This suggests that redundancy of Dvl genes may mask subtle brain abnormalities. Thus we generated Dvl1-/-3+/- mice and tested the development of the neocortex in these mice. We found that Dvl mutant mice displayed early embryonic brain overgrowth associated with induced proliferation and early expansion of basal neural progenitors in vivo and in vitro. In addition, brain overgrowth was associated with expansion of deep layer neurons but not superficial layer neurons. NPC expansion was caused by deregulation of a previously uncharacterized transcriptional cascade downstream of the canonical Wnt pathway. Reduced β-catenin transcriptional activity in the Dvl1-/-3+/- NPCs resulted in down-regulation of Brn2. This relieves the repression of Brn2 on the Tbr2 promoter, which increased Tbr2 expression and the production of basal NPCs. Moreover, Brn2-/- embryos recapitulate the brain overgrowth phenotype. Importantly, preliminary results using pharmacological induction of the Wnt canonical pathway in a short
window during embryonic development rescued the embryonic brain overgrowth phenotype. The rescue of the social behavior phenotypes is currently being tested. These results support a model that spatiotemporal regulation of the β-catenin/Brn2/Tbr2 transcriptional cascade is critical for brain development and may contribute to the social behavioral phenotype in the Dvl mutant mice.
Disclosures:  H. Belinson: None. J. Nakatani: None. R.Y. Birnbaum: None. M. Bershteyn: None. B. Babineau: None. R.J. McEvilly: None. J. Long: None. K. Willert: None. N. Ahituv: None. M.G. Rosenfeld: None. A. Wynshaw-Boris: None.
Keyword(s): AUTISM
DEVELOPMENT
PROLIFERATION
Support: Autism Speaks Translational Postdoc Fellowship #7587
NINDS grants R01 NS073159
NINDS grants R01NS079231
Simons Foundation SFARI #256769




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