AKT activation by N-cadherin regulates beta-catenin signaling and neuronal differentiation during cortical development
1 Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL, 60611, USA
2 Department of Pathology, University of Illinois, 909 S. Wolcott Ave. COMRB 6091, Chicago, IL, 60612, USA
3 Present address: College of Veterinary Medicine and Biomedical Sciences, 1601 Campus Delivery, Colorado State University, Fort Collins, 80523, USA
4 Present address: Center for Rare and Neglected Diseases, Galvin Life Science Building, University of Notre Dame, Notre Dame, 46556, USA
Neural Development 2013, 8:7 doi:10.1186/1749-8104-8-7Published: 25 April 2013
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.
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.
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.