TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system.
TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system.
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TMEM161B 调节发育中的中枢神经系统中的大脑皮质回旋、Sonic Hedgehog 信号传导和纤毛结构。
DOI：
10.1073/pnas.2209964120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
Walsh, Christopher A.
中科院分区：
文献类型：
--
作者：
Akula, Shyam K.;Marciano, Jack H.;Lim, Youngshin;Exposito-Alonso, David;Hylton, Norma K.;Hwang, Grace H.;Neil, Jennifer E.;Dominado, Nicole;Bunton-Stasyshyn, Rosie K.;Song, Janet H. T.;Talukdar, Maya;Schmid, Aloisia;Teboul, Lydia;Mo, Alisa;Shin, Taehwan;Finander, Benjamin;Beck, Samantha G.;Yeh, Rebecca C.;Otani, Aoi;Qian, Xuyu;DeGennaro, Ellen M.;Alkuraya, Fowzan S.;Maddirevula, Sateesh;Cascino, Gregory D.;Giannini, Caterina;Undiagnosed Diseases Network, Lindsay C.;Burrage, Lindsay C.;Rosenfield, Jill A.;Ketkar, Shamika;Clark, Gary D.;Bacino, Carlos;Lewis, Richard A.;Segal, Rosalind A.;Bazan, J. Fernando;Smith, Kelly A.;Golden, Jeffrey A.;Cho, Ginam;Walsh, Christopher A.
通过评估患有皮质折叠畸形的儿童，我们确定了TMEM161B，这是一种功能未知的基因，属于未知的蛋白质超家族。在这项工作中，我们表明，在子宫内破坏Tmem161b足以导致雪貂模型中的回转异常。我们还表征了Tmem161b无效小鼠，其表现出发育异常，包括异常Sonic Hedgehog信号传导的后遗症以及初级纤毛结构的改变。这些连接有助于为Tmem161b的细胞功能提供假设，但也暗示了Sonic Hedgehog信号传导促进人类皮层的正常折叠。Sonic hedgehog信号调节多个组织的胚胎发育过程，但调节上下文特异性Shh信号的因素仍然知之甚少。多小脑回症（皮质折叠紊乱）家族的外显子组测序显示，多个个体在TMEM161B中具有双等位基因有害变体，TMEM161B编码一种功能未知的多通道跨膜蛋白。Tmem161b基因敲除小鼠表现出前脑无裂畸形、颅面中线缺陷、眼缺陷和脊髓模式变化，这些变化与受损的Shh信号传导一致，但没有肢体缺陷，这表明Tmem161b具有CNS特异性作用。在小鼠和雪貂模型中，Tmem161b缺失损害了对体外Smoothened激活的反应，并破坏了体内皮质组织发生，包括导致雪貂模型中的异常回转。Tmem 161 b非排他性地定位于初级纤毛，扫描电子显微镜显示Tmem 161 b缺失小鼠的心室区纤毛缩短、畸形和气球状，这表明Shh相关表型可能反映了纤毛功能障碍。我们的数据确定TMEM 161 B是大脑皮质回转的调节因子，参与初级纤毛结构，是Shh信号传导的调节因子，并进一步暗示Shh信号传导与人类脑回发育有关。
By evaluating children with cortical folding malformations, we identified TMEM161B, a gene with previously unknown function that is part of no known protein superfamily. In this work, we show that disrupting Tmem161b in utero is sufficient to lead to gyration abnormalities in a ferret model. We also characterized a Tmem161b null mouse that demonstrated developmental abnormalities including sequelae of abnormal Sonic Hedgehog signaling as well as alterations of primary ciliary structure. These connections help provide hypotheses for the cellular functions of Tmem161b, but also implicate Sonic Hedgehog signaling in promoting the normal folding of the human cortex. 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.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
7.2
作者：
Christensen, Soren T.;Morthorst, Stine K.;Pedersen, Lotte B.
通讯作者：
Pedersen, Lotte B.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
11.8
作者：
Eisner A;Pazyra-Murphy MF;Durresi E;Zhou P;Zhao X;Chadwick EC;Xu PX;Hillman RT;Scott MP;Greenberg ME;Segal RA
通讯作者：
Segal RA
影响因子：
2.7
作者：
Goodrich, LV;Jung, D;Scott, MP
通讯作者：
Scott, MP