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

Authors

• Phan Q. Duy, Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
• Stefan C. Weise, Molecular Immunology and Cell Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
• Claudia Marini, Institute for Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
• Xiao-Jun Li, Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
• Dan Liang, Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
• Peter J. Dahl, Microbial Sciences Institute, Yale University, West Haven, CT, USA.
• Shaojie Ma, Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
• Ana Spajic, Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
• Weilai Dong, Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
• Jane Juusola, GeneDx, Gaithersburg, MD, USA.
• Emre Kiziltug, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Adam J. Kundishora, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Sunil Koundal, Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA.
• Maysam Z. Pedram, Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA.
• Lucia A. Torres-Fernández, Molecular Immunology and Cell Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
• Kristian Händler, Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.
• Elena De Domenico, Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.
• Matthias Becker, Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.
• Thomas Ulas, Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.
• Stefan A. Juranek, Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
• Elisa Cuevas, Stem Cells and Regenerative Medicine Section, University College London Great Ormond Street Institute of Child Health, London, UK.
• Le Thi Hao, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Bettina Jux, Molecular Immunology and Cell Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
• André M. Sousa, Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
• Fuchen Liu, Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
• Suel-Kee Kim, Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
• Mingfeng Li, Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
• Yiying Yang, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
• Yutaka Takeo, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Alvaro Duque, Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
• Carol Nelson-Williams, Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

Document Type

Article

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.

Medical Subject Headings

Animals; Biomechanical Phenomena; Brain (metabolism); Cerebrospinal Fluid (metabolism); Humans; Hydrocephalus (cerebrospinal fluid, genetics); Mice; Neurogenesis (genetics); Tripartite Motif Proteins (genetics, metabolism); Ubiquitin-Protein Ligases (genetics); Exome Sequencing

Publication Date

4-1-2022

Publication Title

Nature neuroscience

E-ISSN

1546-1726

Volume

25

Issue

4

First Page

458

Last Page

473

PubMed ID

35379995

Digital Object Identifier (DOI)

10.1038/s41593-022-01043-3

Recommended Citation

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.; Liu, Fuchen; Kim, Suel-Kee; Li, Mingfeng; Yang, Yiying; Takeo, Yutaka; Duque, Alvaro; and Nelson-Williams, Carol, "Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus" (2022). Neurosurgery. 2405.
https://scholar.barrowneuro.org/neurosurgery/2405