mTOR regulates brain morphogenesis by mediating GSK3 signaling

Minhan Ka, Gianluigi Condorelli, James R. Woodgett, Woo-Yang Kim

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Balanced control of neural progenitor maintenance and neuron production is crucial in establishing functional neural circuits during brain development, and abnormalities in this process are implicated in many neurological diseases. However, the regulatory mechanisms of neural progenitor homeostasis remain poorly understood. Here, we show that mammalian target of rapamycin (mTOR) is required for maintaining neural progenitor pools and plays a key role in mediating glycogen synthase kinase 3 (GSK3) signaling during brain development. First, we generated and characterized conditional mutant mice exhibiting deletion of mTOR in neural progenitors and neurons in the developing brain using Nestin-cre and Nex-cre lines, respectively. The elimination of mTOR resulted in abnormal cell cycle progression of neural progenitors in the developing brain and thereby disruption of progenitor self-renewal. Accordingly, production of intermediate progenitors and postmitotic neurons were markedly suppressed. Next, we discovered that GSK3, a master regulator of neural progenitors, interacts with mTOR and controls its activity in cortical progenitors. Finally,we found that inactivation ofmTORactivity suppresses the abnormal proliferation of neural progenitors induced by GSK3 deletion. Our findings reveal that the interaction betweenmTOR and GSK3 signaling plays an essential role in dynamic homeostasis of neural progenitors during brain development.

Original languageEnglish (US)
Pages (from-to)4076-4086
Number of pages11
JournalDevelopment (Cambridge)
Volume141
Issue number21
DOIs
StatePublished - Nov 1 2014

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Glycogen Synthase Kinase 3
Sirolimus
Morphogenesis
Brain
Neurons
Homeostasis
Nestin
Cell Cycle
Maintenance

Keywords

  • GSK3
  • Mouse
  • Neural progenitor
  • Neurogenesis
  • Neuron positioning
  • mTOR

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Ka, M., Condorelli, G., Woodgett, J. R., & Kim, W-Y. (2014). mTOR regulates brain morphogenesis by mediating GSK3 signaling. Development (Cambridge), 141(21), 4076-4086. https://doi.org/10.1242/dev.108282

mTOR regulates brain morphogenesis by mediating GSK3 signaling. / Ka, Minhan; Condorelli, Gianluigi; Woodgett, James R.; Kim, Woo-Yang.

In: Development (Cambridge), Vol. 141, No. 21, 01.11.2014, p. 4076-4086.

Research output: Contribution to journalArticle

Ka, M, Condorelli, G, Woodgett, JR & Kim, W-Y 2014, 'mTOR regulates brain morphogenesis by mediating GSK3 signaling', Development (Cambridge), vol. 141, no. 21, pp. 4076-4086. https://doi.org/10.1242/dev.108282
Ka, Minhan ; Condorelli, Gianluigi ; Woodgett, James R. ; Kim, Woo-Yang. / mTOR regulates brain morphogenesis by mediating GSK3 signaling. In: Development (Cambridge). 2014 ; Vol. 141, No. 21. pp. 4076-4086.
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