Abstract
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.
Original language | English |
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Article number | e1081715 |
Number of pages | 10 |
Journal | Neurogenesis |
Volume | 2 |
Issue number | 1 |
DOIs | |
Publication status | Published - 31 Jan 2015 |
Externally published | Yes |
Bibliographical note
Acknowledgments: We thank D. Weinberger, D. St. Clair and D. Valle for discussion, Jaden Shin for gene expression analyses, members of Ming and Song Laboratories for help and critical comments, L. Liu, Y. Cai, Q. Hussaini, and M. Jardine-Alborz for technical support.Funding: This work was supported by NIH (NS048271, MH105128), NARSAD, and MSCRF to G-l.M., by NIH (NS047344 and NS093772) and MSCRF to H.S., by NARSAD and NIH (NS093772) to K.C., and by NARSAD to E.K.
Keywords
- Adult neurogenesis
- DISC1
- Neurodevelopment
- Rheb1