JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell–derived neural progenitors and cortical neurons
Name
e201800094.full.pdf
Description
Published version
Size
2.28 MB
Format
Adobe PDF
Checksum (MD5)
440e00b1f1491bae881e713414261e90
Author(s)
Roessler, Reinhard
Goldmann, Johanna
Shivalila, Chikdu
Jaenisch, Rudolf
Date Issued
June 2018
Journal
Life Science Alliance
Publisher
Life Science Alliance, LLC
Citation
Roessler, Reinhard et al. "JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell–derived neural progenitors and cortical neurons." Life Science Alliance 1, 4 (August 2018): e201800094 © 2018 Roessler et al
Version
Final published version
Abstract
Phelan–McDermid syndrome (also known as 22q13.3 deletion syndrome) is a syndromic form of autism spectrum disorder and currently thought to be caused by heterozygous loss of SHANK3. However, patients most frequently present with large chromosomal deletions affecting several additional genes. We used human pluripotent stem cell technology and genome editing to further dissect molecular and cellular mechanisms. We found that loss of JIP2 (MAPK8IP2) may contribute to a distinct neurodevelopmental phenotype in neural progenitor cells (NPCs) affecting neuronal maturation. This is most likely due to a simultaneous down-regulation of c-Jun N-terminal kinase (JNK) proteins, leading to impaired generation of mature neurons. Furthermore, semaphorin signaling appears to be impaired in patient NPCs and neurons. Pharmacological activation of neuropilin receptor 1 (NRP1) rescued impaired semaphorin pathway activity and JNK expression in patient neurons. Our results suggest a novel disease-specific mechanism involving the JIP/JNK complex and identify NRP1 as a potential new therapeutic target.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.26508/lsa.201800094
