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STRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice
Ksenia A. Orlova, … , Kevin Strauss, Peter B. Crino
Ksenia A. Orlova, … , Kevin Strauss, Peter B. Crino
Published April 26, 2010
Citation Information: J Clin Invest. 2010;120(5):1591-1602. https://doi.org/10.1172/JCI41592.
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STRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice

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Abstract

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 α (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.

Authors

Ksenia A. Orlova, Whitney E. Parker, Gregory G. Heuer, Victoria Tsai, Jason Yoon, Marianna Baybis, Robert S. Fenning, Kevin Strauss, Peter B. Crino

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Figure 5

Knockdown of STRADα ameliorates AICAR-mediated inhibition of mTORC1 signaling in a rapamycin-dependent manner.

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Knockdown of STRADα ameliorates AICAR-mediated inhibition of mTORC1 sign...
(A–L) Transient STRADα knockdown led to hyperphosphorylation of S6 after AICAR treatment. mNPCs were transfected with GFP-shRNA scram (A–C and G–I) or GFP-shRNA STRADα (D–F and J–L), and at 5 DPT were serum starved and treated with either vehicle (A–F) or 2 mM AICAR (G–L) for 12 hours. mNPCs were immunostained for P-S6Ser235/236. Nuclei were visualized with Hoechst (blue, C, F, I, and L). (M) Stable STRADα knockdown in mNPCs prevented AICAR-mediated inhibition of S6 phosphorylation in a rapamycin-dependent manner. Wild-type and stably transfected (puro-shRNA scram and puro-shRNA STRADα) mNPCs were serum starved and treated with 2 mM AICAR for 12 hours, 50 nM rapamycin for 1.5 hours, or 2 mM AICAR for 12 hours followed by 50 nM rapamycin for 1.5 hours. Immunoblotting for P-S6Ser235/236 revealed that STRADα-depleted mNPCs failed to attenuate P-S6 levels after 2 mM AICAR treatment, in contrast to control cells. Rapamycin treatment attenuated P-S6Ser235/236 in STRADα-depleted mNPCs. Immunoblotting for total S6 protein revealed stable S6 expression in all cell types and treatment conditions. Blots were reprobed with β-actin to assess equal loading. Scale bar: 100 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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