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

Phan Q. Duy; Stefan C. Weise; Claudia Marini; Xiao Jun Li; Dan Liang; Peter J. Dahl; Shaojie Ma; Ana Spajic; Weilai Dong; Jane Juusola; Emre Kiziltug; Adam J. Kundishora; Sunil Koundal; Maysam Z. Pedram; Lucia A. Torres-Fernández; Kristian Händler; Elena De Domenico; Matthias Becker; Thomas Ulas; Stefan A. Juranek; Elisa Cuevas; Le Thi Hao; Bettina Jux; André M.M. Sousa; Fuchen Liu; Suel Kee Kim; Mingfeng Li; Yiying Yang; Yutaka Takeo; Alvaro Duque; Carol Nelson-Williams; Yonghyun Ha; Kartiga Selvaganesan; Stephanie M. Robert; Amrita K. Singh; Garrett Allington; Charuta G. Furey; Andrew T. Timberlake; Benjamin C. Reeves; Hannah Smith; Ashley Dunbar; Tyrone DeSpenza; June Goto; Arnaud Marlier; Andres Moreno-De-Luca; Xin Yu; William E. Butler; Bob S. Carter; Evelyn M.R. Lake; R. Todd Constable; Pasko Rakic; Haifan Lin; Engin Deniz; Helene Benveniste; Nikhil S. Malvankar; Juvianee I. Estrada-Veras; Christopher A. Walsh; Seth L. Alper; Joachim L. Schultze; Katrin Paeschke; Angelika Doetzlhofer; F. Gregory Wulczyn; Sheng Chih Jin; Richard P. Lifton; Nenad Sestan; Waldemar Kolanus; Kristopher T. Kahle

doi:10.1038/s41593-022-01043-3

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

Phan Q. Duy, Stefan C. Weise, Claudia Marini, Xiao Jun Li, Dan Liang, Peter J. Dahl, Shaojie Ma, Ana Spajic, Weilai Dong, Jane Juusola, Emre Kiziltug, Adam J. Kundishora, Sunil Koundal, Maysam Z. Pedram, Lucia A. Torres-Fernández, Kristian Händler, Elena De Domenico, Matthias Becker, Thomas Ulas, Stefan A. JuranekElisa Cuevas, Le Thi Hao, Bettina Jux, André M.M. Sousa, Fuchen Liu, Suel Kee Kim, Mingfeng Li, Yiying Yang, Yutaka Takeo, Alvaro Duque, Carol Nelson-Williams, Yonghyun Ha, Kartiga Selvaganesan, Stephanie M. Robert, Amrita K. Singh, Garrett Allington, Charuta G. Furey, Andrew T. Timberlake, Benjamin C. Reeves, Hannah Smith, Ashley Dunbar, Tyrone DeSpenza, June Goto, Arnaud Marlier, Andres Moreno-De-Luca, Xin Yu, William E. Butler, Bob S. Carter, Evelyn M.R. Lake, R. Todd Constable, Pasko Rakic, Haifan Lin, Engin Deniz, Helene Benveniste, Nikhil S. Malvankar, Juvianee I. Estrada-Veras, Christopher A. Walsh, Seth L. Alper, Joachim L. Schultze, Katrin Paeschke, Angelika Doetzlhofer, F. Gregory Wulczyn, Sheng Chih Jin, Richard P. Lifton, Nenad Sestan, Waldemar Kolanus, Kristopher T. Kahle

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	458-473
Number of pages	16
Journal	Nature neuroscience
Volume	25
Issue number	4
DOIs	https://doi.org/10.1038/s41593-022-01043-3
State	Published - Apr 2022

ASJC Scopus subject areas

General Neuroscience

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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., De Domenico, E., Becker, M., Ulas, T., ... Kahle, K. T. (2022). Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus. Nature neuroscience, 25(4), 458-473. https://doi.org/10.1038/s41593-022-01043-3

Duy, PQ, Weise, SC, Marini, C, Li, XJ, Liang, D, Dahl, PJ, Ma, S, Spajic, A, Dong, W, Juusola, J, Kiziltug, E, Kundishora, AJ, Koundal, S, Pedram, MZ, Torres-Fernández, LA, Händler, K, De Domenico, E, Becker, M, Ulas, T, Juranek, SA, Cuevas, E, Hao, LT, Jux, B, Sousa, AMM, Liu, F, Kim, SK, Li, M, Yang, Y, Takeo, Y, Duque, A, Nelson-Williams, C, Ha, Y, Selvaganesan, K, Robert, SM, Singh, AK, Allington, G, Furey, CG, Timberlake, AT, Reeves, BC, Smith, H, Dunbar, A, DeSpenza, T, Goto, J, Marlier, A, Moreno-De-Luca, A, Yu, X, Butler, WE, Carter, BS, Lake, EMR, Constable, RT, Rakic, P, Lin, H, Deniz, E, Benveniste, H, Malvankar, NS, Estrada-Veras, JI, Walsh, CA, Alper, SL, Schultze, JL, Paeschke, K, Doetzlhofer, A, Wulczyn, FG, Jin, SC, Lifton, RP, Sestan, N, Kolanus, W & Kahle, KT 2022, 'Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus', Nature neuroscience, vol. 25, no. 4, pp. 458-473. https://doi.org/10.1038/s41593-022-01043-3

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title = "Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus",

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.",

author = "Duy, {Phan Q.} and Weise, {Stefan C.} and Claudia Marini and Li, {Xiao Jun} and Dan Liang and Dahl, {Peter J.} and Shaojie Ma and Ana Spajic and Weilai Dong and Jane Juusola and Emre Kiziltug and Kundishora, {Adam J.} and Sunil Koundal and Pedram, {Maysam Z.} and Torres-Fern{\'a}ndez, {Lucia A.} and Kristian H{\"a}ndler and {De Domenico}, Elena and Matthias Becker and Thomas Ulas and Juranek, {Stefan A.} and Elisa Cuevas and Hao, {Le Thi} and Bettina Jux and Sousa, {Andr{\'e} M.M.} and Fuchen Liu and Kim, {Suel Kee} and Mingfeng Li and Yiying Yang and Yutaka Takeo and Alvaro Duque and Carol Nelson-Williams and Yonghyun Ha and Kartiga Selvaganesan and Robert, {Stephanie M.} and Singh, {Amrita K.} and Garrett Allington and Furey, {Charuta G.} and Timberlake, {Andrew T.} and Reeves, {Benjamin C.} and Hannah Smith and Ashley Dunbar and Tyrone DeSpenza and June Goto and Arnaud Marlier and Andres Moreno-De-Luca and Xin Yu and Butler, {William E.} and Carter, {Bob S.} and Lake, {Evelyn M.R.} and Constable, {R. Todd} and Pasko Rakic and Haifan Lin and Engin Deniz and Helene Benveniste and Malvankar, {Nikhil S.} and Estrada-Veras, {Juvianee I.} and Walsh, {Christopher A.} and Alper, {Seth L.} and Schultze, {Joachim L.} and Katrin Paeschke and Angelika Doetzlhofer and Wulczyn, {F. Gregory} and Jin, {Sheng Chih} and Lifton, {Richard P.} and Nenad Sestan and Waldemar Kolanus and Kahle, {Kristopher T.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = apr,

doi = "10.1038/s41593-022-01043-3",

language = "English (US)",

volume = "25",

pages = "458--473",

journal = "Nature neuroscience",

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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.

PY - 2022/4

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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.

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JO - Nature neuroscience

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

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