TY  - JOUR
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 Kai Holger
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
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
TI  - Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.
JO  - Nature neuroscience
VL  - 25
IS  - 4
SN  - 1097-6256
CY  - New York, NY
PB  - Nature America
M1  - DZNE-2022-00491
SP  - 458 - 473
PY  - 2022
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.
KW  - Exome Sequencing
KW  - Animals
KW  - Biomechanical Phenomena
KW  - Brain: metabolism
KW  - Cerebrospinal Fluid: metabolism
KW  - Humans
KW  - Hydrocephalus: cerebrospinal fluid
KW  - Hydrocephalus: genetics
KW  - Mice
KW  - Neurogenesis: genetics
KW  - Tripartite Motif Proteins: genetics
KW  - Tripartite Motif Proteins: metabolism
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Whole Exome Sequencing
KW  - Tripartite Motif Proteins (NLM Chemicals)
KW  - TRIM71 protein, human (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9664907
C6  - pmid:35379995
DO  - DOI:10.1038/s41593-022-01043-3
UR  - https://pub.dzne.de/record/163752
ER  -