title: MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection atDrosophilaLarval Neuromuscular Junctions.
abstract: Proper synaptic function in neural circuits requires precise pairings between correct pre- and post-synaptic partners. Errors in this process may underlie development of neuropsychiatric disorders, such as autism spectrum disorder (ASD). Development of ASD can be influenced by genetic factors, including copy number variations (CNVs). In this study, we focused on a CNV occurring at the 16p11.2 locus in the human genome and investigated potential defects in synaptic connectivity caused by reduced activities of genes located in this region atDrosophilalarval neuromuscular junctions, a well-established model synapse with stereotypic synaptic structures. A mutation ofrolled, aDrosophilahomolog of humanmitogen-activated protein kinase 3(MAPK3) at the 16p11.2 locus, caused ectopic innervation of axonal branches and their abnormal defasciculation. The specificity of these phenotypes was confirmed by expression of wild-typerolledin the mutant background. Albeit to a lesser extent, we also observed ectopic innervation patterns in mutants defective in Cdk2, Gαq, and Gp93, all of which were expected to interact with Rolled MAPK3. A further genetic analysis in double heterozygous combinations revealed a synergistic interaction betweenrolledandGp93. In addition, results from RT-qPCR analyses indicated consistently reducedrolledmRNA levels inCdk2,Gαq,andGp93mutants. Taken together, these data suggest a central role of MAPK3 in regulating the precise targeting of presynaptic axons to proper postsynaptic targets, a critical step that may be altered significantly in ASD.
authors.affiliation: Department of Oral Pathology and BK21Plus Project, School of Dentistry, Pusan National University, Yangsan 50612, Korea.
authors.forename: Sang Mee
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Oral Pathology and BK21Plus Project, School of Dentistry, Pusan National University, Yangsan 50612, Korea.|Institute of Translational Dental Sciences, Pusan National University, Yangsan 50612, Korea.
authors.forename: Hae Ryoun
authors.initials: HR
authors.lastname: Park
authors.affiliation: Department of Oral Pathology and BK21Plus Project, School of Dentistry, Pusan National University, Yangsan 50612, Korea.|Institute of Translational Dental Sciences, Pusan National University, Yangsan 50612, Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000201:enzymology* / Q000235:genetics*; D001369:Axons / Q000502:physiology; D023902:Chromosome Pairing / Q000235:genetics; D002885:Chromosomes, Human, Pair 16; D004330:Drosophila; D056426:Genetic Loci; D006801:Humans; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000201:enzymology* / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000502:physiology*
chemical_list: D048052:Mitogen-Activated Protein Kinase 3
keywords: 16p11.2; Drosophila; MAPK3; autism; copy number variations