TY - JOUR
T1 - Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus
AU - Duy, Phan Q.
AU - Weise, Stefan C.
AU - Marini, Claudia
AU - Li, Xiao Jun
AU - Liang, Dan
AU - Dahl, Peter J.
AU - Ma, Shaojie
AU - Spajic, Ana
AU - Dong, Weilai
AU - Juusola, Jane
AU - Kiziltug, Emre
AU - Kundishora, Adam J.
AU - Koundal, Sunil
AU - Pedram, Maysam Z.
AU - Torres-Fernández, Lucia A.
AU - Händler, Kristian
AU - De Domenico, Elena
AU - Becker, Matthias
AU - Ulas, Thomas
AU - Juranek, Stefan A.
AU - Cuevas, Elisa
AU - Hao, Le Thi
AU - Jux, Bettina
AU - Sousa, André M.M.
AU - Liu, Fuchen
AU - Kim, Suel Kee
AU - Li, Mingfeng
AU - Yang, Yiying
AU - Takeo, Yutaka
AU - Duque, Alvaro
AU - Nelson-Williams, Carol
AU - Ha, Yonghyun
AU - Selvaganesan, Kartiga
AU - Robert, Stephanie M.
AU - Singh, Amrita K.
AU - Allington, Garrett
AU - Furey, Charuta G.
AU - Timberlake, Andrew T.
AU - Reeves, Benjamin C.
AU - Smith, Hannah
AU - Dunbar, Ashley
AU - DeSpenza, Tyrone
AU - Goto, June
AU - Marlier, Arnaud
AU - Moreno-De-Luca, Andres
AU - Yu, Xin
AU - Butler, William E.
AU - Carter, Bob S.
AU - Lake, Evelyn M.R.
AU - Constable, R. Todd
AU - Rakic, Pasko
AU - Lin, Haifan
AU - Deniz, Engin
AU - Benveniste, Helene
AU - Malvankar, Nikhil S.
AU - Estrada-Veras, Juvianee I.
AU - Walsh, Christopher A.
AU - Alper, Seth L.
AU - Schultze, Joachim L.
AU - Paeschke, Katrin
AU - Doetzlhofer, Angelika
AU - Wulczyn, F. Gregory
AU - Jin, Sheng Chih
AU - Lifton, Richard P.
AU - Sestan, Nenad
AU - Kolanus, Waldemar
AU - Kahle, Kristopher T.
N1 - Funding Information:
This work was supported by T32GM136651 (to P.Q.D.), F30HD106694 (to P.Q.D.), RO1NS111029 (to K.T.K.), David M. Rubenstein Fund for Hearing Research (to A. Doetzlhofer), 1R21NS121642-01 (to X.Y.), 1R01NS122904-01 (to X.Y.), the Rudi Schulte Institute (to K.T.K.), the Hydrocephalus Association Innovator Award (to K.T.K., E.D. and S.J.C.), 5R21NS116484-02 (to E.D.), National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) Pathway to Independence award R00HL143036-02 (to S.J.C.), Clinical & Translational Research Funding Program award CTSA1405 (to S.J.C.), Children’s Discovery Institute Faculty Scholar award CDI-FR-2021-926 (to S.J.C.), NIH Director’s New Innovator award 1DP2AI138259-01 (to N.S.M.), the Career Award at the Scientific Interfaces from Burroughs Welcome Fund (to N.S.M.), the Hartwell Foundation Individual Biomedical Research Award (to N.S.M.), MacBrainResource NIH MH113257 (to A. Duque), NIH DA023999 (to P.R.) and Deutsche Forschungsgemeinschaft (German Research Foundation) award WU 563/3-1 (to F.G.W.). W.K. is funded by the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy EXC2151–390873048. All mechanical measurements were performed at the Yale West Campus Imaging Core. CSF outflow imaging was performed using the small animal imaging facility of the Center for Precision Cancer Modeling, sponsored by the Yale Cancer Center. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Certain cartoons and diagrams were generated using BioRender.
Funding Information:
This work was supported by T32GM136651 (to P.Q.D.), F30HD106694 (to P.Q.D.), RO1NS111029 (to K.T.K.), David M. Rubenstein Fund for Hearing Research (to A. Doetzlhofer), 1R21NS121642-01 (to X.Y.), 1R01NS122904-01 (to X.Y.), the Rudi Schulte Institute (to K.T.K.), the Hydrocephalus Association Innovator Award (to K.T.K., E.D. and S.J.C.), 5R21NS116484-02 (to E.D.), National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) Pathway to Independence award R00HL143036-02 (to S.J.C.), Clinical & Translational Research Funding Program award CTSA1405 (to S.J.C.), Children?s Discovery Institute Faculty Scholar award CDI-FR-2021-926 (to S.J.C.), NIH Director?s New Innovator award 1DP2AI138259-01 (to N.S.M.), the Career Award at the Scientific Interfaces from Burroughs Welcome Fund (to N.S.M.), the Hartwell Foundation Individual Biomedical Research Award (to N.S.M.), MacBrainResource NIH MH113257 (to A. Duque), NIH DA023999 (to P.R.) and Deutsche Forschungsgemeinschaft (German Research Foundation) award WU 563/3-1 (to F.G.W.). W.K. is funded by the Deutsche Forschungsgemeinschaft under Germany?s Excellence Strategy EXC2151?390873048. All mechanical measurements were performed at the Yale West Campus Imaging Core. CSF outflow imaging was performed using the small animal imaging facility of the Center for Precision Cancer Modeling, sponsored by the Yale Cancer Center. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Certain cartoons and diagrams were generated using BioRender.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85127575066&partnerID=8YFLogxK
U2 - 10.1038/s41593-022-01043-3
DO - 10.1038/s41593-022-01043-3
M3 - Article
C2 - 35379995
AN - SCOPUS:85127575066
SN - 1097-6256
VL - 25
SP - 458
EP - 473
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 4
ER -