TMEM161B modulates radial glial scaffolding in neocortical development

TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b 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 TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.

Automated summary

TMEM161B is a widely expressed transmembrane protein of unknown function in human, and mutations in this gene cause recessive polymicrogyria (PMG) and intellectual disability. Studies in mice and patient-derived brain organoids show that TMEM161B is involved in the development of the neocortex through regulation of apical cell polarity and radial glial scaffolding. TMEM161B modulates actin filopodia, acting upstream of the Rho-GTPase CDC42. These findings link TMEM161B to human PMG and provide insights into the role of TMEM161B in neocortical development.