Journal Article

DZNE-2022-00491

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.

Duy, P. Q. ; Weise, S. C. ; Marini, C. ; Li, X.-J. ; Liang, D. ; Dahl, P. J. ; Ma, S. ; Spajic, A. ; Dong, W. ; Juusola, J. ; Kiziltug, E. ; Kundishora, A. J. ; Koundal, S. ; Pedram, M. Z. ; Torres-Fernández, L. A. ; Händler, K.DZNE* ; de Domenico, E.DZNE* ; Becker, M. K. H.DZNE* ; Ulas, T.DZNE* ; Juranek, S. A. ; Cuevas, E. ; Hao, L. T. ; Jux, B. ; Sousa, A. M. M. ; Liu, F. ; Kim, S.-K. ; Li, M. ; Yang, Y. ; Takeo, Y. ; Duque, A. ; Nelson-Williams, C. ; Ha, Y. ; Selvaganesan, K. ; Robert, S. M. ; Singh, A. K. ; Allington, G. ; Furey, C. G. ; Timberlake, A. T. ; Reeves, B. C. ; Smith, H. ; Dunbar, A. ; DeSpenza, T. ; Goto, J. ; Marlier, A. ; Moreno-De-Luca, A. ; Yu, X. ; Butler, W. E. ; Carter, B. S. ; Lake, E. M. R. ; Constable, R. T. ; Rakic, P. ; Lin, H. ; Deniz, E. ; Benveniste, H. ; Malvankar, N. S. ; Estrada-Veras, J. I. ; Walsh, C. A. ; Alper, S. L. ; Schultze, J.DZNE* ; Paeschke, K. ; Doetzlhofer, A. ; Wulczyn, F. G. ; Jin, S. C. ; Lifton, R. P. ; Sestan, N. ; Kolanus, W. ; Kahle, K. T.

2022
Nature America New York, NY

This record in other databases:    

Please use a persistent id in citations: doi:10.1038/s41593-022-01043-3

Abstract: 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.

Keyword(s): Exome Sequencing (MeSH) ; Animals (MeSH) ; Biomechanical Phenomena (MeSH) ; Brain: metabolism (MeSH) ; Cerebrospinal Fluid: metabolism (MeSH) ; Humans (MeSH) ; Hydrocephalus: cerebrospinal fluid (MeSH) ; Hydrocephalus: genetics (MeSH) ; Mice (MeSH) ; Neurogenesis: genetics (MeSH) ; Tripartite Motif Proteins: genetics (MeSH) ; Tripartite Motif Proteins: metabolism (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Whole Exome Sequencing (MeSH) ; Tripartite Motif Proteins ; TRIM71 protein, human ; Ubiquitin-Protein Ligases

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Contributing Institute(s):

1. United epigenomic platform (AG Schultze)
2. Platform for Single Cell Genomics and Epigenomics at DZNE & University of Bonn (R&D PRECISE)
3. Modular High Performance Computing and Artificial Intelligence (Modular High Performance Computing)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 25 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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