Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 20, Pages 5746-5758Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv295
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Funding
- National Institutes of Health [R01 NS086329]
- McKnight Endowment Fund for Neuroscience award
- China Scholarship Council
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Abnormal axonal connectivity and hyperactive mTOR complex 1 (mTORC1) are shared features of several neurological disorders. Hyperactive mTORC1 alters axon length and polarity of hippocampal neurons in vitro, but the impact of hyperactive mTORC1 on axon growth in vivo and the mechanisms underlying those effects remain unclear. Using in utero electroporation during corticogenesis, we show that increasing mTORC1 activity accelerates axon growth without multiple axon formation. This was prevented by counteracting mTORC1 signaling through p70S6Ks (S6K1/2) or eukaryotic initiation factor 4E-binding protein (4E-BP1/2), which both regulate translation. In addition to regulating translational targets, S6K1 indirectly signals through GSK3 beta, a regulator of axogenesis. Although blocking GSK3 beta activity did not alter axon growth under physiological conditions in vivo, blocking it using a dominant-negative mutant or lithium chloride prevented mTORC1-induced accelerated axon growth. These data reveal the contribution of translational and non-translational downstream effectors such as GSK3 beta to abnormal axon growth in neurodevelopmental mTORopathies and open new therapeutic options for restoring long-range connectivity.
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