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

Autor: Akula SK; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Harvard-Massachusetts Institute of Technology MD/PhD Program, Program in Neuroscience, Harvard Medical School, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Marciano JH; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Lim Y; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Exposito-Alonso D; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Hylton NK; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Harvard-Massachusetts Institute of Technology MD/PhD Program, Program in Neuroscience, Harvard Medical School, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Hwang GH; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Neurobiology, Harvard Medical School, Boston, MA 02115., Neil JE; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115., Dominado N; Department of Anatomy & Physiology, The University of Melbourne, Melbourne, VIC 3010, Australia., Bunton-Stasyshyn RK; Mary Lyon Centre, United Kingdom Medical Research Council Harwell, Didcot, Oxfordshire, OX11 0RD, UK., Song JHT; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Talukdar M; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Harvard-Massachusetts Institute of Technology MD/PhD Program, Program in Neuroscience, Harvard Medical School, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Schmid A; Department of Physics/Electron Microscopy Core, Northeastern University, Boston, MA 02115., Teboul L; Mary Lyon Centre, United Kingdom Medical Research Council Harwell, Didcot, Oxfordshire, OX11 0RD, UK., Mo A; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115., Shin T; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Finander B; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Beck SG; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115., Yeh RC; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115., Otani A; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115., Qian X; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115., DeGennaro EM; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Alkuraya FS; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, 11564 Riyadh, Saudi Arabia., Maddirevula S; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, 11564 Riyadh, Saudi Arabia., Cascino GD; Department of Neurology, Mayo Clinic, Rochester, MN 55905., Giannini C; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905., Burrage LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.; Departments of Pediatrics, Baylor College of Medicine, Houston, TX 77030.; Neurology, Baylor College of Medicine, Houston, TX 77030.; Neuroscience, Baylor College of Medicine, Houston, TX 77030., Rosenfield JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030., Ketkar S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030., Clark GD; Departments of Pediatrics, Baylor College of Medicine, Houston, TX 77030.; Neurology, Baylor College of Medicine, Houston, TX 77030.; Neuroscience, Baylor College of Medicine, Houston, TX 77030., Bacino C; Departments of Pediatrics, Baylor College of Medicine, Houston, TX 77030.; Neurology, Baylor College of Medicine, Houston, TX 77030.; Neuroscience, Baylor College of Medicine, Houston, TX 77030., Lewis RA; Departments of Pediatrics, Baylor College of Medicine, Houston, TX 77030.; Neurology, Baylor College of Medicine, Houston, TX 77030.; Neuroscience, Baylor College of Medicine, Houston, TX 77030., Segal RA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Neurobiology, Harvard Medical School, Boston, MA 02115., Bazan JF; Unit for Structural Biology, Vlaams Instituut voor Biotechnologie-UGent Center for Inflammation Research, 9052 Ghent, Belgium., Smith KA; Department of Anatomy & Physiology, The University of Melbourne, Melbourne, VIC 3010, Australia., Golden JA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Cho G; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Walsh CA; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.; Harvard-Massachusetts Institute of Technology MD/PhD Program, Program in Neuroscience, Harvard Medical School, Boston, MA 02115.; Howard Hughes Medical Institute, Boston Children's Hospital Boston, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Department of Neurology, Harvard Medical School, Boston, MA 02115.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jan 24; Vol. 120 (4), pp. e2209964120. Date of Electronic Publication: 2023 Jan 20.
DOI: 10.1073/pnas.2209964120
Abstrakt: 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.
Databáze: MEDLINE
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