Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:57 |
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| Enthalten in: |
Developmental cell - 57(2022), 20 vom: 24. Okt., Seite 2381-2396.e13 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Qian, Xuyu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.10.2022 Date Revised 16.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.devcel.2022.09.011 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM347436978 |
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| 100 | 1 | |a Qian, Xuyu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis |
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| 500 | |a Date Completed 27.10.2022 | ||
| 500 | |a Date Revised 16.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a apoptosis | |
| 650 | 4 | |a cerebral cortex | |
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| 700 | 1 | |a Talukdar, Maya |e verfasserin |4 aut | |
| 700 | 1 | |a Akula, Shyam K |e verfasserin |4 aut | |
| 700 | 1 | |a Lai, Abbe |e verfasserin |4 aut | |
| 700 | 1 | |a Shao, Diane D |e verfasserin |4 aut | |
| 700 | 1 | |a Gonzalez, Dilenny |e verfasserin |4 aut | |
| 700 | 1 | |a Marciano, Jack H |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Richard S |e verfasserin |4 aut | |
| 700 | 1 | |a Hylton, Norma K |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Edward |e verfasserin |4 aut | |
| 700 | 1 | |a Bazan, J Fernando |e verfasserin |4 aut | |
| 700 | 1 | |a Barrett, Lee |e verfasserin |4 aut | |
| 700 | 1 | |a Yeh, Rebecca C |e verfasserin |4 aut | |
| 700 | 1 | |a Hill, R Sean |e verfasserin |4 aut | |
| 700 | 1 | |a Beck, Samantha G |e verfasserin |4 aut | |
| 700 | 1 | |a Otani, Aoi |e verfasserin |4 aut | |
| 700 | 1 | |a Angad, Jolly |e verfasserin |4 aut | |
| 700 | 1 | |a Mitani, Tadahiro |e verfasserin |4 aut | |
| 700 | 1 | |a Posey, Jennifer E |e verfasserin |4 aut | |
| 700 | 1 | |a Pehlivan, Davut |e verfasserin |4 aut | |
| 700 | 1 | |a Calame, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Aydin, Hatip |e verfasserin |4 aut | |
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| 700 | 1 | |a Im, Kiho |e verfasserin |4 aut | |
| 700 | 1 | |a Taranath, Ajay |e verfasserin |4 aut | |
| 700 | 1 | |a Scott, Hamish S |e verfasserin |4 aut | |
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