title: AKT activation by N-cadherin regulates beta-catenin signaling and neuronal differentiation during cortical development.
abstract: 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.
authors.affiliation: Department of Pathology, University of Illinois, 909 S, Wolcott Ave., Chicago, IL 60612, USA.
authors.forename: Jianing
authors.initials: J
authors.lastname: Zhang
authors.forename: Julie R
authors.initials: JR
authors.lastname: Shemezis
authors.forename: Erin R
authors.initials: ER
authors.lastname: McQuinn
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Maria
authors.initials: M
authors.lastname: Sverdlov
authors.forename: Anjen
authors.initials: A
authors.lastname: Chenn
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3