Caveat mTOR: aberrant signaling disrupts corticogenesis.
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 alpha (STRADalpha), and Orlova et al. show that reduction of STRADalpha 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 STRADalpha 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.
Osborne
Lucy R
LR
Department of Medicine and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. lucy.osborne@utoronto.ca
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002465:Cell Movement; D004827:Epilepsy / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007859:Learning Disabilities / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D033942:Adaptor Proteins, Vesicular Transport; D047908:Intracellular Signaling Peptides and Proteins; C518004:STRAD protein, mouse; D011494:Protein Kinases; C420464:sterile 20-like protein kinase nerve injury-associated kinase; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases