Dataset Information

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, G?_q, 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, G?_q, 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.

SUBMITTER: Park SM

PROVIDER: S-EPMC5339506 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at <i>Drosophila</i> Larval Neuromuscular Junctions.

Park Sang Mee SM Park Hae Ryoun HR Lee Ji Hye JH

Molecules and cells 20170215 2

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 ...[more]

PMID: 28196412

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Project description:Trans-synaptic interactions involving Neurexins and Neuroligins are thought to promote adhesive interactions for precise alignment of the pre- and postsynaptic compartments and organize synaptic macromolecular complexes across species. In Drosophila, while Neurexin (Dnrx) and Neuroligins (Dnlg) are emerging as central organizing molecules at synapses, very little is known of the spectrum of proteins that might be recruited to the Dnrx/Dnlg trans-synaptic interface for organization and growth of the synapses. Using full length and truncated forms of Dnrx and Dnlg1 together with cell biological analyses and genetic interactions, we report novel functions of Dnrx and Dnlg1 in clustering of pre- and postsynaptic proteins, coordination of synaptic growth and ultrastructural organization. We show that Dnrx and Dnlg1 extracellular and intracellular regions are required for proper synaptic growth and localization of Dnlg1 and Dnrx, respectively. dnrx and dnlg1 single and double mutants display altered subcellular distribution of Discs large (Dlg), which is the homolog of mammalian post-synaptic density protein, PSD95. dnrx and dnlg1 mutants also display ultrastructural defects ranging from abnormal active zones, misformed pre- and post-synaptic areas with underdeveloped subsynaptic reticulum. Interestingly, dnrx and dnlg1 mutants have reduced levels of the Bone Morphogenetic Protein (BMP) receptor Wishful thinking (Wit), and Dnrx and Dnlg1 are required for proper localization and stability of Wit. In addition, the synaptic overgrowth phenotype resulting from the overexpression of Dnrx fails to manifest in wit mutants. Phenotypic analyses of dnrx/wit and dnlg1/wit mutants indicate that Dnrx/Dnlg1/Wit coordinate synaptic growth and architecture at the NMJ. Our findings also demonstrate that loss of Dnrx and Dnlg1 leads to decreased levels of the BMP co-receptor, Thickveins and the downstream effector phosphorylated Mad at the Neuromuscular Junction (NMJ) synapses indicating that Dnrx/Dnlg1 regulate components of the BMP signaling pathway. Together our findings reveal that Dnrx/Dnlg are at the core of a highly orchestrated process that combines adhesive and signaling mechanisms to ensure proper synaptic organization and growth during NMJ development.

Dataset Information

MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval Neuromuscular Junctions.

Publications

MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at <i>Drosophila</i> Larval Neuromuscular Junctions.

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