1. TMEM161B modulates radial glial scaffolding in neocortical development
- Author
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Wang, Lu, Heffner, Caleb, Vong, Keng loi, Barrows, Chelsea, Ha, Yoo-Jin, Lee, Sangmoon, Lara-Gonzalez, Pablo, Jhamb, Ishani, Van Der Meer, Dennis, Loughnan, Robert, Parker, Nadine, Sievert, David, Mittal, Swapnil, Issa, Mahmoud Y, Andreassen, Ole A, Dale, Anders, Dobyns, William B, Zaki, Maha S, Murray, Stephen A, and Gleeson, Joseph G
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Genetics ,Clinical Research ,Intellectual and Developmental Disabilities (IDD) ,Brain Disorders ,Neurological ,Animals ,Humans ,Mice ,Ependymoglial Cells ,Mice ,Knockout ,Neocortex ,TMEM161B ,gyrification ,CDC42 ,knock-in crispant mice ,patient-derived brain organoids - 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.
- Published
- 2023