Rheb1 mediates DISC1-dependent regulation of new neuron development in the adult hippocampus.
A large number of susceptibility genes have been implicated in psychiatric disorders with a developmental origin, yet their biological roles and signaling mechanisms in neurodevelopment are largely unknown. Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for several major psychiatric disorders, regulates the development of newborn neurons in the adult hippocampus. Systemic pharmacological inhibition of mTOR signaling with rapamycin has been shown to rescue DISC1 deficiency-induced neurodevelopmental defects, as well as cognitive and affective deficits. Whether mTOR signaling plays a cell-autonomous and/or non-cell-autonomous role in DISC1-dependent regulation of neuronal development is not clear. Here we provide genetic evidence that hyper-activation of mTOR activator Rheb1 (Ras homolog enriched in brain 1) in newborn neurons recapitulates DISC1 deficiency-induced neurodevelopmental defects, including neuronal morphogenesis and migration. We further show that genetic deletion of Rheb1 rescues those defects in a cell-autonomous fashion in developing newborn neurons in the adult hippocampus. Our genetic and functional studies demonstrate that Rheb1 acts as a key mediator of DISC1-dependent regulation of mTOR signaling and neuronal development during adult hippocampal neurogenesis.
Institute for Cell Engineering; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; These authors contributed equally to this work.
Eunchai
E
Kang
Institute for Cell Engineering; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; These authors contributed equally to this work.
Ju Young
JY
Kim
Institute for Cell Engineering; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA.
Cindy Y
CY
Liu
The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; The State Key Laboratory of Biotherapy; West China Hospital; Sichuan University; Chengdu P.R. China.
Bo
B
Xiao
Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine ; Baltimore, MD USA.
Po Yu
PY
Chen
Institute for Cell Engineering; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA.
Kimberly M
KM
Christian
Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine; Baltimore, MD USA.
Paul F
PF
Worley
Institute for Cell Engineering; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine; Baltimore, MD USA.
Hongjun
H
Song
Institute for Cell Engineering; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; Department of Neurology; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; The Solomon H. Snyder Department of Neuroscience; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA; Graduate Program in Cellular and Molecular Medicine; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine; Baltimore, MD USA; Department of Psychiatry and Behavioral Sciences; Johns Hopkins University School of Medicine; Baltimore, MD USA.
Guo-Li
GL
Ming
DISC1; Rheb1; adult neurogenesis; neurodevelopment