DISC1 Regulates New Neuron Development in the Adult Brain via Modulation of AKT-mTOR Signaling through KIAA1212

Ju Young Kim, Xin Duan, Cindy Y. Liu, Mi-Hyeon D Jang, Junjie U. Guo, Nattapol Pow-anpongkul, Eunchai Kang, Hongjun Song, Guo li Ming

Research output: Contribution to journalArticle

238 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)761-773
Number of pages13
JournalNeuron
Volume63
Issue number6
DOIs
StatePublished - Sep 24 2009
Externally publishedYes

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Keywords

  • DEVBIO
  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Kim, J. Y., Duan, X., Liu, C. Y., Jang, M-H. D., Guo, J. U., Pow-anpongkul, N., Kang, E., Song, H., & Ming, G. L. (2009). DISC1 Regulates New Neuron Development in the Adult Brain via Modulation of AKT-mTOR Signaling through KIAA1212. Neuron, 63(6), 761-773. https://doi.org/10.1016/j.neuron.2009.08.008