JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse

•JAKMIP1 is a novel component of an FMRP-associated RNP complex•JAKMIP1 binds synaptic mRNAs and PSD proteins implicated in ASD•JAKMIP1 regulates neuronal translation and glutamatergic signaling•JAKMIP1 knockout results in core ASD behaviors in the mouse

SummaryAutism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders.