Abstract
Significance
Neocortical folding (i.e., gyrification) is a fundamental evolutionary mechanism allowing the expansion of cortical surface area and increased cognitive function. Increased gyrification has been correlated with intelligence across species but has been difficult to study molecularly in non-gyrated animal models. Here we identify a role for TMEM161B in human gyrification, establishing cellular polarity and structural integrity of radial glial fibers of the developing brain.
Abstract
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.