TMEM161B modulates radial glial scaffolding in neocortical development.

Wang, Lu; Heffner, Caleb; Vong, Keng Ioi; Barrows, Chelsea; Ha, Yoo-Jin; Lee, Sangmoon; Lara-Gonzalez, Pablo; Jhamb, Ishani et al. · Proc Natl Acad Sci U S A · 2023

basic_science · Level V

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Abstract

<i>TMEM161B</i> encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify <i>TMEM161B</i> homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying <i>TMEM161B</i> mutations exhibit striking neocortical PMG and intellectual disability. <i>Tmem161b</i> knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link <i>TMEM161B</i> with human PMG, likely regulating radial glia apical polarity during neocortical development.

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