JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell-derived neural progenitors and cortical neurons

Abstract

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.peer-reviewed)

Genotype–phenotype correlation in Phelan‐McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes

“…MAPK8IP2 − / − mice exhibit prominent deficits in locomotor activity and ataxic gait, in addition to defective social interactions and learning (Giza et al, 2010). Even just the hemizygous loss of MAPK8IP2 causes impaired neuronal maturation (Roessler et al, 2018). PLXNB2 codes for one of the Plexins (Plxn), large transmembrane receptors for semaphorins (Sema).…”

“…RABL2B knockout mice display a phenotype typical of ciliopathies, similar to Bardet‐Biedl Syndrome; however, to this date, human ciliopathies have not unveiled mutations in this gene (Kanie et al, 2017). MAPK8IP2 is involved in early neurodevelopment (Roessler et al, 2018) and MAPK8IP2 − / − mice show autistic‐like behaviors (Giza et al, 2010). Altered social behavior and neurocognitive deficits relevant to schizophrenia, accompanied by loss of striatal parvalbumin‐containing interneurons, have also been recorded in BRD1 + / − mice (Qvist et al, 2017; 2018).…”