Caveat mTOR: aberrant signaling disrupts corticogenesis
Lucy R. Osborne
Lucy R. Osborne
Published April 26, 2010
Citation Information: J Clin Invest. 2010;120(5):1392-1395. https://doi.org/10.1172/JCI43030.
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Commentary

Caveat mTOR: aberrant signaling disrupts corticogenesis

Abstract

The mammalian target of rapamycin (mTOR) signaling pathway is activated in several disorders associated with benign tumors and malformations of the cerebral cortex. In this issue of the JCI, Orlova et al. have now definitively added another disorder to this group by demonstrating that activation of mTOR signaling is associated with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE), which is characterized by severe intractable epilepsy and megalencephaly. PMSE is caused by lack of the pseudokinase STE20-related kinase adaptor α (STRADα), and Orlova et al. show that reduction of STRADα levels during corticogenesis in the mouse results in a cellular phenotype and neuronal migration defects similar to those observed in patients with PMSE, clearly demonstrating a pivotal role for STRADα in cell polarity and growth. This study helps pave the way for possible therapeutic intervention with rapamycin to control the epilepsy and learning disabilities associated with this disorder.

Authors

Lucy R. Osborne

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Figure 1

mTOR signaling pathway is involved in genetic syndromes.

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mTOR signaling pathway is involved in genetic syndromes. Shown is the re...
Shown is the relationship among different proteins encoded by genes known to be responsible for genetic syndromes associated with activation of mTORC1. Activation of mTORC1 ultimately leads to increased protein synthesis, and thereby increased cell growth. Germline mutations that result in mTORC1 hyperactivation are therefore associated with syndromes characterized by cellular overgrowth, usually in the form of hamartomas. LKB1 also activates an mTORC1-independent pathway that controls neuronal polarity specification; it is therefore possible that the neuronal migration defects seen in individuals with PMSE may be due to effects on this pathway, and not to hyperactivation of mTOR signaling. This would explain the lack of neuronal migration defects in disorders associated with germline mutations that do not affect LKB1 localization or function. 4E-BP1, eIF4E-binding protein 1; eIF4E, eukaryotic translation initiation factor 4E; MAP, microtubule-associate protein; PDK1, phosphoinositide-dependent protein kinase–1; Rheb, Ras homolog enriched in brain; S6K1, S6 kinase, 70 kDa, polypeptide 1.