MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval 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 at Drosophila larval neuromuscular junctions, a well-established model synapse with stereotypic synaptic structures. A mutation of rolled, a Drosophila homolog of human mitogen-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-type rolled in 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 between rolled and Gp93. In addition, results from RT-qPCR analyses indicated consistently reduced rolled mRNA levels in Cdk2, Gαq, and Gp93 mutants. 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.

Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity

“…Among the genes with recurrent mutation and CNV intersection, MAPK3 is particularly interesting with respect to the chromosome 16p11.2 microduplication. Several functional studies on 16p11.2 deletion and duplication mice as well as Drosophila models have suggested that MAPK3 is a key regulator of the syndrome: being downstream of other ASD target genes; involved in axon targeting and regulation of cortical cytoarchitecture; and being the most topologically important gene in the region by PPIs 85-87 . Our analysis builds on these studies by providing evidence of recurrent missense mutation enrichment in human NDDs.…”

Atypical neural variability in carriers of 16p11.2 copy number variants

“…This CNV is associated with a variable phenotype, in terms of the clinical profile and degree of symptom severity [Golzio & Katsanis, ; D'angelo et al, ; Snyder et al, ; Steinman et al, ]. The 16p11.2 chromosomal region spans approximately 29 genes, including MAPK3 and MVP —both potentially influencing synaptic function and cortical plasticity [Park, Park, & Lee, ]. The loss (DEL) or gain (DUP) of these ~29 genes in the 16p11.2 has a population prevalence of ~0.05% for DEL and ~0.04% for DUP [Kirov et al, ].…”

Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolescent Trio-Based Sample

“…Moreover, the protein encoded by MAPK7 is a member of the MAPK family involved in a wide variety of cellular processes, such as proliferation, differentiation, transcription regulation, and brain development (Pearson et al 2001), and abnormalities in these processes can lead to the development of ASD symptoms (Nagy et al 2017;Courchesne et al 2019). Previous evidence also indicated rare mutations in the MAPK gene family participating in ASD, such as MAPK3 (Park et al 2017) and MAPK1 knockout mice showing ASD-like behavior (Satoh et al 2011). Together with these results of de novo SNVs in MAPK7, it may be inferred from this study that mutations in the MAPK family may involve the genes that affect multiple cellular processes, resulting in the inability of cells to develop and mature normally, leading to the onset of ASD.…”