PT  - JOURNAL ARTICLE
AU  - Reinhard Roessler
AU  - Johanna Goldmann
AU  - Chikdu Shivalila
AU  - Rudolf Jaenisch
TI  - JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell-derived neural progenitors and cortical neurons
AID  - 10.1101/196535
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 196535
4099  - http://biorxiv.org/content/early/2017/09/30/196535.short
4100  - http://biorxiv.org/content/early/2017/09/30/196535.full
AB  - Phelan-McDermid syndrome (also known as 22q13 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 progenitors (NPCs) affecting neuronal maturation. This is most likely due to simultaneous misregulation of JNK proteins, leading to impaired generation of mature neurons. Furthermore, semaphorin signaling is compromised in patient NPCs and neurons. Pharmacological stimulation 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 potential therapeutic target.