DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212.
Disrupted-in-schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here, we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to overactivated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies the AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.
Kim
Ju Young
JY
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Duan
Xin
X
Liu
Cindy Y
CY
Jang
Mi-Hyeon
MH
Guo
Junjie U
JU
Pow-anpongkul
Nattapol
N
Kang
Eunchai
E
Song
Hongjun
H
Ming
Guo-li
GL
D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding / Q000235:genetics; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D014162:Transfection / Q000379:methods
C498794:Disc1 protein, mouse; D007166:Immunosuppressive Agents; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; D051058:Oncogene Protein v-akt; D020123:Sirolimus