Journal article
TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system
SK Akula, JH Marciano, Y Lim, D Exposito-Alonso, NK Hylton, GH Hwang, JE Neil, N Dominado, RK Bunton-Stasyshyn, JHT Song, M Talukdar, A Schmid, L Teboul, A Mo, T Shin, B Finander, SG Beck, RC Yeh, A Otani, X Qian Show all
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2023
Abstract
Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B, which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothene..
View full abstractGrants
Awarded by Broad Institute
Funding Acknowledgements
We are grateful the participant families involved in this study. We are grateful to Annapurna Poduri, Gord Fishell, Lisa Goodrich, Xuecai Ge, Rajat Rohatgi, Jennifer Kong, Lu Wang, and to other members of the Joseph Gleeson Lab for helpful discussions during planning of experiments and data interpretation. We thank Swati P. Iyer for assistance with mice. We are grateful to Andrew C. Kay for design consultation and illustration support. S.K.A. is supported by the Harvard Stem Cell Institute, NIH T32 MH020017 and T32 GM007753, and the Paul and Daisy Soros Fellowship for New Americans. D.E-A. is supported by an EMBO Postdoctoral Fellowship ALTF 336-2022. X.Q. is funded by a Postdoctoral Fellowship from the Helen Hay Whitney Foundation and the HHMI. R.A.S and G.H.H. are supported by Alex's Lemonade Stand Foundation, The Swifty Foundation, and the Helen Gurley Pussycat Foundation. Exome sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900. C.A.W. is supported by the NINDS (R01 NS035129) and J.A.G. is supported by the NINDS (R01NS100007). This work was supported by UM1HG006348. C.A.W. is supported by the Allen Discovery Center for Human Brain Evolution through The Paul G. Allen Frontiers Group. C.A.W. is an Investigator of the HHMI.