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

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

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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.

Original languageEnglish
Pages (from-to)458-473
Number of pages16
JournalNature neuroscience
Issue number4
StatePublished - Apr 2022


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