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 of mTOR activity suppresses the abnormal proliferation of neural progenitors induced by GSK3 deletion. Our findings reveal that the interaction between mTOR and GSK3 signaling plays an essential role in dynamic homeostasis of neural progenitors during brain development.
Highlights
Normal development of the brain, more than any other organ, requires precise control of the self-renewal and differentiation of neural progenitors to establish functional circuitry
Expression of phosphorylated forms of mammalian target of rapamycin (mTOR), 4EBP1, S6 and S6K were concentrated at the ventricular surfaces (Fig. 1A,B), indicating that the mTOR signal is activated in radial neural progenitors
We explore the potential roles of mTOR in glycogen synthase kinase 3 (GSK3) signaling during neural progenitor development, we first examined whether GSK3 controls the activity of mTOR signaling using GSK3-deleted brains
Summary
Normal development of the brain, more than any other organ, requires precise control of the self-renewal and differentiation of neural progenitors to establish functional circuitry. The signaling network playing a decisive role in homeostatic control of balancing progenitors and neurons in the developing brain is poorly understood. Recent studies suggest that mTOR signaling is involved in neural development (Hartman et al, 2013; Hentges et al, 1999, 2001; Rennebeck et al, 1998; Way et al, 2009). There is lack of in vivo genetic evidence that defines mTOR functions by deleting mTOR in neural progenitors and neurons during brain formation
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