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TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system

2023; National Academy of Sciences; Volume: 120; Issue: 4 Linguagem: Inglês

10.1073/pnas.2209964120

1091-6490

Shyam K. Akula, Jack H. Marciano, Youngshin Lim, David Exposito-Alonso, Norma K. Hylton, Grace H. Hwang, Jennifer E. Neil, Nicole Dominado, Rosie Bunton-Stasyshyn, Janet Song, Maya Talukdar, Aloisia Schmid, Lydia Teboul, Alisa Mo, Taehwan Shin, Benjamin Finander, Samantha G. Beck, Rebecca C. Yeh, Aoi Otani, Xuyu Qian, Ellen M. DeGennaro, Fowzan S. Alkuraya, Sateesh Maddirevula, Gregory D. Cascino, Caterina Giannini, Lindsay C. Burrage, Jill A. Rosenfield, Shamika Ketkar, Gary Clark, Carlos A. Bacino, Richard A. Lewis, Rosalind A. Segal, J. Fernando Bazán, K. A. Smith, Jeffrey A. Golden, Ginam Cho, Christopher A. Walsh, David R. Adams, Aaron W. Aday, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Eva H. Baker, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David Bick, Camille L. Birch, Devon Bonner, Braden Boone, Bret L. Bostwick, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Shan Chen, Gary Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jean M. Davidson, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina M. Dipple, Naghmeh Dorrani, Daniel C. Dorset, Jessica Douglas, Emilie D. Douine, David D. Draper, Annika M. Dries, David J. Eckstein, Lisa Emrick, Christine M. Eng, Gregory M. Enns, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Liliana Fernández, Carlos R. Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine Groden, Andrea Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Frances A. High, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Fariha Jamal, Yong‐hui Jiang, Jean M. Johnston, Angela Jones, Lefkothea Karaviti, Emily G. Kelley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Donna M. Krasnewich, Joel B. Krier, Jennifer Kyle, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan Lee, Hane Lee, Shawn Levy, Richard A. Lewis, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Martín G. Martín, Julián A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie‐Rosell, Colleen E. McCormack, Alexa T. McCray, Jason D. Merker, Thomas Metz, Matthew Might, Ganeshwaran H. Mochida, Paolo Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Jennifer L. Murphy, Donna M. Muzny, Michele Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, James P. Orengo, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Loren D.M. Peña, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, David A. Sweetser, Queenie K.‐G. Tan, Wen-Haan Tan, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Éric Vilain, Tiphanie P. Vogel, Daryl Waggott, Colleen E. Wahl, Melissa Walker, Sophie Nicole, Jijun Wan, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie‐Jo Webb‐Robertson, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, Allison Zheng,

Genetic and Kidney Cyst Diseases

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 Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.