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DOI 10.1038/s41593-022-01043-3

Медицинская библиотека · Nature neuroscience · 2022

Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.

Duy Phan Q, Weise Stefan C, Marini Claudia, Li Xiao-Jun, Liang Dan, Dahl Peter J, Ma Shaojie, Spajic Ana, Dong Weilai, Juusola Jane, Kiziltug Emre, Kundishora Adam J, Koundal Sunil, Pedram Maysam Z, Torres-Fernández Lucia A, Händler Kristian, De Domenico Elena, Becker Matthias, Ulas Thomas, Juranek Stefan A, Cuevas Elisa, Hao Le Thi, Jux Bettina, Sousa André M M, Liu Fuchen, Kim Suel-Kee, Li Mingfeng, Yang Yiying, Takeo Yutaka, Duque Alvaro, Nelson-Williams Carol, Ha Yonghyun, Selvaganesan Kartiga, Robert Stephanie M, Singh Amrita K, Allington Garrett, Furey Charuta G, Timberlake Andrew T, Reeves Benjamin C, Smith Hannah, Dunbar Ashley, DeSpenza Tyrone, Goto June, Marlier Arnaud, Moreno-De-Luca Andres, Yu Xin, Butler William E, Carter Bob S, Lake Evelyn M R, Constable R Todd, Rakic Pasko, Lin Haifan, Deniz Engin, Benveniste Helene, Malvankar Nikhil S, Estrada-Veras Juvianee I, Walsh Christopher A, Alper Seth L, Schultze Joachim L, Paeschke Katrin, Doetzlhofer Angelika, Wulczyn F Gregory, Jin Sheng Chih, Lifton Richard P, Sestan Nenad, Kolanus Waldemar, Kahle Kristopher T

СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаПеревод в очереди

Аннотация

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

Для цитирования: Duy Phan Q, Weise Stefan C, Marini Claudia, Li Xiao-Jun, Liang Dan, Dahl Peter J, Ma Shaojie, Spajic Ana, Dong Weilai, Juusola Jane, Kiziltug Emre, Kundishora Adam J, Koundal Sunil, Pedram Maysam Z, Torres-Fernández Lucia A, Händler Kristian, De Domenico Elena, Becker Matthias, Ulas Thomas, Juranek Stefan A, Cuevas Elisa, Hao Le Thi, Jux Bettina, Sousa André M M, Liu Fuchen, Kim Suel-Kee, Li Mingfeng, Yang Yiying, Takeo Yutaka, Duque Alvaro, Nelson-Williams Carol, Ha Yonghyun, Selvaganesan Kartiga, Robert Stephanie M, Singh Amrita K, Allington Garrett, Furey Charuta G, Timberlake Andrew T, Reeves Benjamin C, Smith Hannah, Dunbar Ashley, DeSpenza Tyrone, Goto June, Marlier Arnaud, Moreno-De-Luca Andres, Yu Xin, Butler William E, Carter Bob S, Lake Evelyn M R, Constable R Todd, Rakic Pasko, Lin Haifan, Deniz Engin, Benveniste Helene, Malvankar Nikhil S, Estrada-Veras Juvianee I, Walsh Christopher A, Alper Seth L, Schultze Joachim L, Paeschke Katrin, Doetzlhofer Angelika, Wulczyn F Gregory, Jin Sheng Chih, Lifton Richard P, Sestan Nenad, Kolanus Waldemar, Kahle Kristopher T. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.. Nature neuroscience. 2022. DOI: 10.1038/s41593-022-01043-3.

Предметные рубрики MeSH

AnimalsBiomechanical PhenomenaBrainCerebrospinal FluidHumansHydrocephalusMiceNeurogenesisTripartite Motif ProteinsUbiquitin-Protein LigasesExome Sequencing
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