TMEM161B modulates radial glial scaffolding in neocortical development

Lu Wang, Caleb Heffner, Keng loi Vong, Chelsea Barrows, Yoo Jin Ha, Sangmoon Lee, Pablo Lara-Gonzalez, Ishani Jhamb, Dennis Van Der Meer, Robert Loughnan, Nadine Parker, David Sievert, Swapnil Mittal, Mahmoud Y. Issa, Ole A. Andreassen, Anders Dale, William B. Dobyns, Maha S. Zaki, Stephen A. Murray, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere2209983120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number4
DOIs
StatePublished - Jan 24 2023

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. L.W. received support from NIH/NINDS Pathway to independent K99/R00 award (1K99NS125106-01A1), CIRM Training Grant Postdoc

Funding Information:
award (EDUC4-12804) and the BBRF (grant 28771).Y.-J.H received funding from Ministry of Health & Welfare, Republic of Korea (HI19C1330). We acknowledge Drs. Trey Ideker, Sangwoo Kim, and members of the Gleeson Lab for feedback, Gene Matcher for connecting us with Drs. Shyam Akula and Christopher A. Walsh and Dr. Kelly Smith for communicating preliminary data. This work was supported by the Rady Children’s Hospital Neuroscience Endowment and the HHMI to J.G.G., the UCSD Microscopy Core (NINDS grant P30NS047101), CCBB supported by NIH grant UL1TR001442, CIRM grant IT1-06611 for generation of IPCSs, the Yale, GMKF and NIH X01HG011360 to support genotyping at CIDR, NIH X01HD100698 to support genome sequencing, Broad Institute Center for Mendelian Genomics NIH grant UM1HG008900, and OD030187 to C.H. and S.A.M. for generation of mice models, the generation of CRISPR/Cas9 edited embryos was supported in part by the Genetic Engineering Technology core and Cancer Center Support grant (CA034196), O.A.A. obtained support from the Research Council of Norway (#223273).

Publisher Copyright:
Copyright © 2023 the Author(s).

Keywords

  • CDC42
  • TMEM161B
  • gyrification
  • knock-in crispant mice
  • patient-derived brain organoids

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