Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.
Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.
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DOI：
10.1038/s41593-022-01043-3
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发表时间：
2022-04
影响因子：
25
通讯作者：
Kahle, Kristopher T.
中科院分区：
文献类型：
--
作者：
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-Fernandez, Lucia A.;Haendler, Kristian;De Domenico, Elena;Becker, Matthias;Ulas, Thomas;Juranek, Stefan A.;Cuevas, Elisa;Hao, Le Thi;Jux, Bettina;Sousa, Andre 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, Jr.;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.
以脑室扩张为特征的脑积水通常归因于脑脊液（CSF）稳态的原发性缺陷。这促使CSF分流成为儿童脑外科手术的主要原因，尽管存在相当大的疾病异质性。在这项研究中，通过整合人脑转录组学与483例先天性脑积水（CH）患者的全外显子组测序，我们发现胚胎神经上皮干细胞中CH风险基因的会聚。在所有CH风险基因中，TRIM 71/lin-41具有最多的从头突变，并且最特异性地在神经上皮细胞中表达。携带神经上皮细胞特异性Trim 71缺失或CH特异性Trim 71突变的小鼠表现出产前脑积水。CH突变破坏TRIM 71与其RNA靶点的结合，导致神经上皮细胞过早分化和神经发生减少。皮质发育不全导致皮质过度顺应性和继发性脑室扩大，而脑脊液循环无原发性缺陷。这些数据突出了精确调节神经上皮细胞命运对正常脑-CSF生物力学的重要性，并支持CH的临床相关神经祖细胞为基础的范例。
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.
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影响因子：
15.9
作者：
DeSpenza T Jr;Carlson M;Panchagnula S;Robert S;Duy PQ;Mermin-Bunnell N;Reeves BC;Kundishora A;Elsamadicy AA;Smith H;Ocken J;Alper SL;Jin SC;Hoffman EJ;Kahle KT
通讯作者：
Kahle KT
影响因子：
12.3
作者：
Dong J;Hu Y;Fan X;Wu X;Mao Y;Hu B;Guo H;Wen L;Tang F
通讯作者：
Tang F
影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
16.2
作者：
Duran, Daniel;Zeng, Xue;Kahle, Kristopher T.
通讯作者：
Kahle, Kristopher T.
影响因子：
1.2
作者：
Canovic, Elizabeth Peruski;Qing, Bo;Van Vliet, Krystyn J.
通讯作者：
Van Vliet, Krystyn J.