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

作者：Zhang Jianing; Shemezis Julie R; McQuinn Erin R; Wang Jing; Sverdlov Maria; Chenn Anjen^*

来源：Neural Development, 2013, 8(1): 7.

DOI：10.1186/1749-8104-8-7

• Adherens junctions
• AKT
• beta-catenin
• ventricular zone
• Radial glia
• Neuronal differentiation

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 beta-catenin signaling, but the underlying mechanisms remained poorly understood.
Results: Here, with conditional knockout approaches, we find further supporting evidence that N-cadherin maintains beta-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 beta-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 beta-catenin via AKT, as reduction of N-cadherin causes decreased AKT activation and reduced phosphorylation of AKT targets GSK3 beta and beta-catenin. Inhibition of AKT signaling in neural precursors in vivo leads to reduced beta-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 beta-catenin signaling through both Wnt and AKT, and suggest a previously unrecognized role for AKT in neuronal differentiation and cell survival during cortical development.

• 出版日期2013-4-25
• 单位西北大学