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

• Published in: Nature neuroscience Vol. 25; no. 4; pp. 458 - 473
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2022; Nature Publishing Group
• Subjects: 631/136/368/2430; 631/208/191; 692/699/375/240; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomechanical Phenomena; Biomechanics; Biomedical and Life Sciences; Biomedicine; Brain; Brain - metabolism; Cell differentiation; Cell fate; Cerebrospinal fluid; Cerebrospinal Fluid - metabolism; Clonal deletion; Defects; Differentiation (biology); Embryo cells; Exome Sequencing; Experimental research; Gene deletion; Genes; Heterogeneity; Homeostasis; Humans; Hydrocephalus; Hydrocephalus - cerebrospinal fluid; Hydrocephalus - genetics; Hypoplasia; Mice; Mutation; Neurobiology; Neurogenesis; Neurogenesis - genetics; Neurosciences; Stem cell transplantation; Stem cells; Transcriptomics; Tripartite Motif Proteins - genetics; Tripartite Motif Proteins - metabolism; Ubiquitin-Protein Ligases - genetics; Ventricle
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-022-01043-3

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.
Duy and Weise et al. combined human functional integrative genomics with mouse experimental biology to reveal a neuroprogenitor-based genetic subtype of human hydrocephalus with defective neurogenesis and altered brain–fluid biomechanics.