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Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor a (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADα normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADα expression. STRADα-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADα in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADα deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE., Introduction Rare disorders of central nervous system development can provide novel insights into normal brain formation during embryogenesis. Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE; colloquially referred to as pretzel [...]

Hemimegalencephaly (HMEG) is a developmental brain malformation characterized by unilateral hemispheric enlargement, cytoarchitectural abnormalities, and an association with epilepsy. To define the developmental pathogenesis of HMEG, the expression of 200 cell signaling, growth, angiogenic, and transcription factor genes was assayed in HMEG samples (n=8) with targeted cDNA arrays. Differential expression of 31 mRNAs across the 4 gene families was identified in HMEG compared with control cortex. Increases in growth and transcription factor genes included JNK-1, cyclic AMP response element binding protein (CREB), and tuberin mRNAs and decreases included insulin-like growth factor-1 (IGF-1), transforming growth factor beta-3 (TGF-beta3), and NFkB mRNAs. Increased expression of cyclin D1, c-myc, and WISP-1 mRNAs in HMEG suggested activation of the Wnt-1/beta-catenin cascade. Western analysis demonstrated increased levels of non-phosphorylated beta-catenin, which transcriptionally activates cyclin D7 and c-myc genes, but reduced levels of Ser33/Ser37/Thr41 phospho-beta-catenin, which is essential for beta-catenin-inactivation, in HMEG. Altered expression of 31 mRNAs from 4 gene families in human HMEG may lead to aberrant cell growth and hemispheric enlargement during brain development. Enhanced cyclin D1 and c-myc transcription likely reflects increased transcriptionally active beta-catenin due to decreased Ser33/Ser37/Thr41 phospho-beta-catenin and suggests activation of the Wnt-1/beta-catenin cascade in HMEG.