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

Jamee M Berg; Changhoon Lee; Leslie Chen; Laurie Galvan; Carlos Cepeda; Jane Y Chen; Olga Peñagarikano; Jason L Stein; Alvin Li; Asami Oguro-Ando; Jeremy A Miller; Ajay A Vashisht; Mary E Starks; Elyse P Kite; Eric Tam; Amos Gdalyahu; Noor B Al-Sharif; Zachary D Burkett; Stephanie A White; Scott C Fears; Michael S Levine; James A Wohlschlegel; Daniel H Geschwind

doi:10.1016/j.neuron.2015.10.031

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

Neuron. 2015 Dec 16;88(6):1173-1191. doi: 10.1016/j.neuron.2015.10.031. Epub 2015 Nov 25.

Authors

Jamee M Berg¹, Changhoon Lee², Leslie Chen², Laurie Galvan³, Carlos Cepeda³, Jane Y Chen³, Olga Peñagarikano², Jason L Stein², Alvin Li², Asami Oguro-Ando², Jeremy A Miller², Ajay A Vashisht⁴, Mary E Starks², Elyse P Kite², Eric Tam², Amos Gdalyahu⁵, Noor B Al-Sharif³, Zachary D Burkett⁶, Stephanie A White⁶, Scott C Fears³, Michael S Levine³, James A Wohlschlegel⁴, Daniel H Geschwind⁷

Affiliations

¹ Interdepartmental Program for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Interdepartmental Program in Molecular, Cellular, and Integrative Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment and Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dhg@mednet.ucla.edu.

Abstract

Autism 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / physiology*
Animals
Autism Spectrum Disorder / genetics*
Autism Spectrum Disorder / metabolism*
Gene Regulatory Networks / physiology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons / physiology
Protein Biosynthesis / physiology*
Proteomics / methods
RNA-Binding Proteins / physiology*
Synapses / physiology*

Substances

Adaptor Proteins, Signal Transducing
JAKMIP1 protein, human
RNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding