Neural stem cells (NSCs) lie at the core of brain development and repair, and alterations in NSC self-renewal anddifferentiation can have major consequences on brain function at any stage of life. As a result, a series of extracellular signals tightly regulate NSC self-renewal and differentiation at different stages of brain development. Many of these extracellular signals subsequently activate the mTORC1 signaling pathway, which is an intracellular hub of translational regulation that is dysregulated in several neurological diseases and aging.
Despite a wealth of studies related to the impact of hyperactive mTORC1 on brain development in vivo and to some extent NSC behavior in vitro, very little is known about the physiological function of mTORC1 on NSC self-renewal and neuron production in vivo. Here, we explore mTORC1 and its downstream effectors’ function on neonatal NSCs in the subventricular zone (SVZ), a neurogenic niche that confers a high degree of plasticity for circuit remodeling and repair after birth.
In vivoelectroporation in neonates was used to transfectexpression or knockdown vectors selectively in neonatal NSCs and manipulate the activity of mTORC1 and its downstream effectors, the translational repressor 4E-BP1/2 and p70 S6K1/2. We found that decreasing mTORC1 activity prevented the generation of intermediate progenitors leading to reduced neuron production. Consistent with this finding, increasing mTORC1 activity did not induce NSC proliferation, but induced their terminal differentiation into highly proliferative intermediate progenitors, leading to an apparent increase in the number of proliferative cells. The hyperactive mTORC1 effect was mediated by 4E-BP2 but not S6K1/2 emphasizing the importance of 4E-BP2 pathway and cap-dependent translation in regulating NSC self-renewal and differentiation. Collectively, these findings explain how aging leads to NSC exhaustion through mTORC1 and identify 4E-BP2 as a target of choice for preventing or rescuing abnormal brain development.
Research Interests :
Neuroscience, Cellular & Molecular Physiology
Awards and Honors:
- 2012 International Society of Neurochemistry (ISN)-Wiley-Blackwell-Journal of neurochemistry (JNC)-International Lectureship award
- 2010 McKnight Neuroscience of brain Disorder Award (selected 3/100)
- 2003 Young Investigator Travel Award to the American Epilepsy Society Meeting
- 2002 Epilepsy Foundation Junior Faculty Research Award. Acknowledged in a press release in The Yale bulletin and Calendar journal (volume 31, #1).
- 2000 Junior Investigator Award, Amyotrophic Lateral Sclerosis Association