Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis

Xuyu Qian; Ellen M. DeGennaro; Maya Talukdar; Shyam K. Akula; Abbe Lai; Diane D. Shao; Dilenny Gonzalez; Jack H. Marciano; Richard S. Smith; Norma K. Hylton; Edward Yang; J. Fernando Bazan; Lee Barrett; Rebecca C. Yeh; R. Sean Hill; Samantha G. Beck; Aoi Otani; Jolly Angad; Tadahiro Mitani; Jennifer E. Posey; Davut Pehlivan; Daniel Calame; Hatip Aydin; Osman Yesilbas; Kendall C. Parks; Emanuela Argilli; Eleina England; Kiho Im; Ajay Taranath; Hamish S. Scott; Christopher P. Barnett; Peer Arts; Elliott H. Sherr; James R. Lupski; Christopher A. Walsh

doi:10.1016/j.devcel.2022.09.011

Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis

Xuyu Qian, Ellen M. DeGennaro, Maya Talukdar, Shyam K. Akula, Abbe Lai, Diane D. Shao, Dilenny Gonzalez, Jack H. Marciano, Richard S. Smith, Norma K. Hylton, Edward Yang, J. Fernando Bazan, Lee Barrett, Rebecca C. Yeh, R. Sean Hill, Samantha G. Beck, Aoi Otani, Jolly Angad, Tadahiro Mitani, Jennifer E. PoseyDavut Pehlivan, Daniel Calame, Hatip Aydin, Osman Yesilbas, Kendall C. Parks, Emanuela Argilli, Eleina England, Kiho Im, Ajay Taranath, Hamish S. Scott, Christopher P. Barnett, Peer Arts, Elliott H. Sherr, James R. Lupski, Christopher A. Walsh^*

^*Corresponding author for this work

Pharmacology

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

11 Scopus citations

Abstract

Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.

Original language	English (US)
Pages (from-to)	2381-2396.e13
Journal	Developmental Cell
Volume	57
Issue number	20
DOIs	https://doi.org/10.1016/j.devcel.2022.09.011
State	Published - Oct 24 2022

Funding

We thank Boston Children’s Hospital (BCH) Assay Development & Screening Core Facility and Harvard Medical School Biopolymer Core Facility for the technical help. We thank Jennifer E. Neil at BCH and Barbara Pirgousis at Women’s and Children’s Hospital, North Adelaide, SA, Australia for help coordinating the patient information. Figure 7 J was created in part with BioRender.com . X.Q. was funded by a postdoctoral fellowship from the Simons Center for the Social Brain at the Massachusetts Institute of Technology and a postdoctoral fellowship from the Helen Hay Whitney Foundation and the Howard Hughes Medical Institute. E.M.D. was supported by the Surpina and Panos Eurnekian Bio Fund Fellowship. M.T. was supported by the National Institute of General Medical Sciences (NIGMS) Medical Scientist Training Program ( T32 GM007753 and T32 GM144273 ). S.K.A. is supported by a Paul and Daisy Soros Fellowship. D.D.S. was supported by NINDS Neurology Resident Research Education Program ( R25 NS070682 ). N.K.H. was supported by NIGMS Medical Scientist Training Program ( T32GM007753 and T32GM144273 ). The analysis for SHE_1305 was funded by the NHGRI , NEI , and NHLBI grant UM1 HG008900 and in part by NHGRI grant R01 HG009141 ; BAB10995 and BAB5949 by NINDS : R35NS105078 , NHGRI : UM1HG006542 , U01HG011758 , NIGMS : R01GM106373 , and the Uehara Memorial Foundation . The BCH Human Neuron Core was funded by IDDRC U54HD090255 . C.A.W. was supported by R01NS035129 and R01NS032457 from the NINDS and by the Allen Discovery Center program , a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation . C.A.W. is an Investigator of the Howard Hughes Medical Institute. We thank Boston Children's Hospital (BCH) Assay Development & Screening Core Facility and Harvard Medical School Biopolymer Core Facility for the technical help. We thank Jennifer E. Neil at BCH and Barbara Pirgousis at Women's and Children's Hospital, North Adelaide, SA, Australia for help coordinating the patient information. Figure 7J was created in part with BioRender.com. X.Q. was funded by a postdoctoral fellowship from the Simons Center for the Social Brain at the Massachusetts Institute of Technology and a postdoctoral fellowship from the Helen Hay Whitney Foundation and the Howard Hughes Medical Institute. E.M.D. was supported by the Surpina and Panos Eurnekian Bio Fund Fellowship. M.T. was supported by the National Institute of General Medical Sciences (NIGMS) Medical Scientist Training Program (T32 GM007753 and T32 GM144273). S.K.A. is supported by a Paul and Daisy Soros Fellowship. D.D.S. was supported by NINDS Neurology Resident Research Education Program (R25 NS070682). N.K.H. was supported by NIGMS Medical Scientist Training Program (T32GM007753 and T32GM144273). The analysis for SHE_1305 was funded by the NHGRI, NEI, and NHLBI grant UM1 HG008900 and in part by NHGRI grant R01 HG009141; BAB10995 and BAB5949 by NINDS: R35NS105078, NHGRI: UM1HG006542, U01HG011758, NIGMS: R01GM106373, and the Uehara Memorial Foundation. The BCH Human Neuron Core was funded by IDDRC U54HD090255. C.A.W. was supported by R01NS035129 and R01NS032457 from the NINDS and by the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation. C.A.W. is an Investigator of the Howard Hughes Medical Institute. X.Q. and C.A.W. designed the research. X.Q. E.M.D. S.K.A. D.D.S. D.G. J.H.M. R.S.S. R.C.Y. S.G.B. N.K.H. and A.O. performed the research. X.Q. E.M.D. M.T. S.K.A. R.S.S. J.F.B. L.B. and K.I. analyzed data. E.Y. J.A. T.M. J.E.P. D.P. K.C.P. E.A. E.E. A.T. H.S.S. C.P.B. P.A. E.H.S. and J.R.L. contributed clinical and genetic data. A.L. D.D.S. and R.S.H. coordinated clinical data. X.Q. E.M.D. S.K.A. A.L. and C.A.W. wrote the paper. J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories, and J.R.L. is a member of the Scientific Advisory Board of BG. C.A.W. has stock ownership in Maze Therapeutics and is a paid consultant for Third Rock Ventures and Flagship Pioneering.

Keywords

apoptosis
cerebral cortex
congenital brain malformation
corpus callosum
development
genetics
kinesin
migration
organoid

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.devcel.2022.09.011

Cite this

Qian, X., DeGennaro, E. M., Talukdar, M., Akula, S. K., Lai, A., Shao, D. D., Gonzalez, D., Marciano, J. H., Smith, R. S., Hylton, N. K., Yang, E., Bazan, J. F., Barrett, L., Yeh, R. C., Hill, R. S., Beck, S. G., Otani, A., Angad, J., Mitani, T., ... Walsh, C. A. (2022). Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis. Developmental Cell, 57(20), 2381-2396.e13. https://doi.org/10.1016/j.devcel.2022.09.011

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title = "Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis",

abstract = "Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.",

keywords = "apoptosis, cerebral cortex, congenital brain malformation, corpus callosum, development, genetics, kinesin, migration, organoid",

author = "Xuyu Qian and DeGennaro, {Ellen M.} and Maya Talukdar and Akula, {Shyam K.} and Abbe Lai and Shao, {Diane D.} and Dilenny Gonzalez and Marciano, {Jack H.} and Smith, {Richard S.} and Hylton, {Norma K.} and Edward Yang and Bazan, {J. Fernando} and Lee Barrett and Yeh, {Rebecca C.} and Hill, {R. Sean} and Beck, {Samantha G.} and Aoi Otani and Jolly Angad and Tadahiro Mitani and Posey, {Jennifer E.} and Davut Pehlivan and Daniel Calame and Hatip Aydin and Osman Yesilbas and Parks, {Kendall C.} and Emanuela Argilli and Eleina England and Kiho Im and Ajay Taranath and Scott, {Hamish S.} and Barnett, {Christopher P.} and Peer Arts and Sherr, {Elliott H.} and Lupski, {James R.} and Walsh, {Christopher A.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = oct,

day = "24",

doi = "10.1016/j.devcel.2022.09.011",

language = "English (US)",

volume = "57",

pages = "2381--2396.e13",

journal = "Developmental Cell",

issn = "1534-5807",

publisher = "Cell Press",

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Qian, X, DeGennaro, EM, Talukdar, M, Akula, SK, Lai, A, Shao, DD, Gonzalez, D, Marciano, JH, Smith, RS, Hylton, NK, Yang, E, Bazan, JF, Barrett, L, Yeh, RC, Hill, RS, Beck, SG, Otani, A, Angad, J, Mitani, T, Posey, JE, Pehlivan, D, Calame, D, Aydin, H, Yesilbas, O, Parks, KC, Argilli, E, England, E, Im, K, Taranath, A, Scott, HS, Barnett, CP, Arts, P, Sherr, EH, Lupski, JR & Walsh, CA 2022, 'Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis', Developmental Cell, vol. 57, no. 20, pp. 2381-2396.e13. https://doi.org/10.1016/j.devcel.2022.09.011

TY - JOUR

T1 - Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis

AU - Qian, Xuyu

AU - DeGennaro, Ellen M.

AU - Talukdar, Maya

AU - Akula, Shyam K.

AU - Lai, Abbe

AU - Shao, Diane D.

AU - Gonzalez, Dilenny

AU - Marciano, Jack H.

AU - Smith, Richard S.

AU - Hylton, Norma K.

AU - Yang, Edward

AU - Bazan, J. Fernando

AU - Barrett, Lee

AU - Yeh, Rebecca C.

AU - Hill, R. Sean

AU - Beck, Samantha G.

AU - Otani, Aoi

AU - Angad, Jolly

AU - Mitani, Tadahiro

AU - Posey, Jennifer E.

AU - Pehlivan, Davut

AU - Calame, Daniel

AU - Aydin, Hatip

AU - Yesilbas, Osman

AU - Parks, Kendall C.

AU - Argilli, Emanuela

AU - England, Eleina

AU - Im, Kiho

AU - Taranath, Ajay

AU - Scott, Hamish S.

AU - Barnett, Christopher P.

AU - Arts, Peer

AU - Sherr, Elliott H.

AU - Lupski, James R.

AU - Walsh, Christopher A.

PY - 2022/10/24

Y1 - 2022/10/24

N2 - Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.

AB - Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.

KW - apoptosis

KW - cerebral cortex

KW - congenital brain malformation

KW - corpus callosum

KW - development

KW - genetics

KW - kinesin

KW - migration

KW - organoid

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U2 - 10.1016/j.devcel.2022.09.011

DO - 10.1016/j.devcel.2022.09.011

M3 - Article

C2 - 36228617

AN - SCOPUS:85140735533

SN - 1534-5807

VL - 57

SP - 2381-2396.e13

JO - Developmental Cell

JF - Developmental Cell

IS - 20

ER -

Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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