Emerging roles for MAP kinases in agrin signaling

Abstract

Information between neurons and the target cells they innervated passes through sites of functional contact called synapses. How synapses form and are altered by sensory or cognitive experience is central to understand nervous system function. Studies of synapse formation and plasticity have concentrated on a few "model" synapses. The vertebrate neuromuscular junction (NMJ), the synapse between a motoneuron in the spinal cord and a skeletal muscle fiber, is one such model synapse. The extracellular matrix proteoglycan agrin plays an essential organizing role at the NMJ. Agrin is also present at some synapses in the brain and in other organs in the periphery, but its function outside the NMJ is unclear. The core signaling pathway for agrin at the NMJ, which is still incompletely defined, includes molecules specifically involved in this cascade and molecules used in other signaling pathways in many cells. Mitogen-activated protein kinases (MAPKs) are evolutionarily conserved components of intracellular signaling modules that control a myriad of cellular processes. This article reviews emerging evidence that suggests that MAPKs are involved in agrin signaling at the NMJ and in the putative functions of agrin in the formation of a subset of synapses in the brain.

Acknowledgements

I thank Earl Godfrey for critically reading the manuscript. Supported by Texas A&M Health Science Center start-up funds.

Figures and Tables

Figure 1 Simplified diagrams for agrin-induced signaling. (A) At the NMJ secreted agrin-z⁺ binds to Lrp4 and activates (arrows) MuSK and Dok-7. Rac/Cdc42 is activated dowstream of Dok-7, which leads to AChR clustering, to activation of MAP2K7, JNK and ultimately to transcriptional stimulation of postsynaptic genes such as MuSK and AChR subunits. Agrin-z⁺-induced Lrp4/MuSK activation also stimulates MEK1/2 and ERK1/2 transiently (thinner arrows), which activates a negative feedback loop that inhibits AChR clustering (T-shape line). For much more detailed diagrams of agrin signaling at the NMJ please see reference 55. (B) In cortical and/or hippocampal neurons that bear excitatory synapses, soluble agrin-z⁺ may bind to Lrp4/MuSK, which might activate ERK1/2, which in turn would phosphorylate CREB. Phosphorylated CREB would stimulate transcription of genes that directly or indirectly influence synaptogenesis or synapse stability (i.e., “synaptic” genes). Electrical activity-dependent cleavage of full-length agrin (N-agrin-C) in the ECM by neurotrypsin releases a 22-kDa C-terminal fragment (agrin-C) that may bind α3 Na⁺/K⁺-ATPase (NKA), to stimulate filopodial formation. The involvement of MAPKs in this pathway is unknown (MAPKs?). An unknown ligand may bind to transmembrane agrin (TM agrin), leading to formation of dendritic filopodia via activation of ERK1/2 dowstream of the Src-family tyrosine kinase Fyn. (?) These steps have not been confirmed experimentally. For references see text.