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Figure 3 | Molecular Autism

Figure 3

From: A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism

Figure 3

Simplified schematic illustrating molecular mechanisms of neurite regulation. Extracellular events such as cell contact [79], guidance cues [64], neurotransmitter release [80], and interactions with extracellular matrix components [46] are detected by receptors and cell adhesion molecules at the membrane surface and are transduced via cytoplasmic terminals and multidomain scaffolding proteins [47] to downstream signalling molecules [8183]. Polarity and directional navigation is achieved by coordinating local calcium concentration [84], Src family kinases [85], cyclic nucleotide activation (cAMP and cGMP) [86], and phosphoinositide signalling molecules which affect the spatial distribution and membrane recruitment of proteins that regulate the neuronal cytoskeleton [87]. Chief among these regulators are the small Rho family GTPases RhoA, Rac and Cdc42, which serve as molecular 'switches' to activate downstream effectors of cytoskeletal remodelling [88]. In developed neurons, this pathway further regulates the formation of actin-dependent microarchitecture such as mushroom-like dendritic spines at the postsynaptic terminals of excitatory and inhibitory synapses [89]. This simplified schematic presents components in an exploded format for tractability, and includes an abridged set of interactions. Additional File 9 presents autism candidate genes identified by GWAS-NR having known roles in neurite regulation. RPTP (receptor protein tyrosine phosphatase); EphR (Eph receptor); FGFR (fibroblast growth factor receptor); EphR (Eph receptor); PLXN (plexin); NRP (neuropilin); Trk (neurotrophin receptor); ECM (extracellular matrix); NetR (netrin receptor); NMDAR (NMDA receptor); mGluR (metabotropic glutamate receptor); AA (arachidonic acid); PLCγ (phospholipase C, gamma); MAGI (membrane associated guanylate kinase homolog); IP3 (inositol 1,4,5-trisphosphate); DAG (diacylglycerol); PIP2 (phosphatidylinositol 4,5-bisphosphate); PIP3 (phosphatidylinositol 3,4,5-trisphosphate); PI3K (phosphoinositide-3-kinase); nNOS (neuronal nitric oxide synthase); NO (nitric oxide); IP3R (inositol trisphosphate receptor); RyR (ryanodine receptor); GEF (guanine exchange factor); GAP (GTPase activating protein); MAPK (mitogen-activated protein kinase); and JNK (c-Jun N-terminal kinase).

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