AKT activation by N-cadherin regulates beta-catenin signaling and neuronal differentiation during cortical development

Neural Development

Anjen Chenn⁴  Maria Sverdlov⁴  Jing Wang¹  Erin R McQuinn²  Julie R Shemezis⁴  Jianing Zhang³ 

[1] Present address: Center for Rare and Neglected Diseases, Galvin Life Science Building, University of Notre Dame, Notre Dame, 46556, USA;Present address: College of Veterinary Medicine and Biomedical Sciences, 1601 Campus Delivery, Colorado State University, Fort Collins, 80523, USA;Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL, 60611, USA;Department of Pathology, University of Illinois, 909 S. Wolcott Ave. COMRB 6091, Chicago, IL, 60612, USA

关键词: Neuronal differentiation;    Radial glia;    ventricular zone;    β-catenin;    AKT;    Adherens junctions;   

Others  :  806258
DOI  :  10.1186/1749-8104-8-7

 received in 2012-10-17, accepted in 2013-04-05,  发布年份 2013

【 摘 要 】

Background

During cerebral cortical development, neural precursor-precursor interactions in the ventricular zone neurogenic niche coordinate signaling pathways that regulate proliferation and differentiation. Previous studies with shRNA knockdown approaches indicated that N-cadherin adhesion between cortical precursors regulates β-catenin signaling, but the underlying mechanisms remained poorly understood.

Results

Here, with conditional knockout approaches, we find further supporting evidence that N-cadherin maintains β-catenin signaling during cortical development. Using shRNA to N-cadherin and dominant negative N-cadherin overexpression in cell culture, we find that N-cadherin regulates Wnt-stimulated β-catenin signaling in a cell-autonomous fashion. Knockdown or inhibition of N-cadherin with function-blocking antibodies leads to reduced activation of the Wnt co-receptor LRP6. We also find that N-cadherin regulates β-catenin via AKT, as reduction of N-cadherin causes decreased AKT activation and reduced phosphorylation of AKT targets GSK3β and β-catenin. Inhibition of AKT signaling in neural precursors in vivo leads to reduced β-catenin-dependent transcriptional activation, increased migration from the ventricular zone, premature neuronal differentiation, and increased apoptotic cell death.

Conclusions

These results show that N-cadherin regulates β-catenin signaling through both Wnt and AKT, and suggest a previously unrecognized role for AKT in neuronal differentiation and cell survival during cortical development.

【 授权许可】

   
2013 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

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