Regulation of axonal outgrowth and pathfinding by integrin–ecm interactions

Abstract

Developing neurons use a combination of guidance cues to assemble a functional neural network. A variety of proteins immobilized within the extracellular matrix (ECM) provide specific binding sites for integrin receptors on neurons. Integrin receptors on growth cones associate with a number of cytosolic adaptor and signaling proteins that regulate cytoskeletal dynamics and cell adhesion. Recent evidence suggests that soluble growth factors and classic axon guidance cues may direct axon pathfinding by controlling integrin-based adhesion. Moreover, since classic axon guidance cues themselves are immobilized within the ECM and integrins modulate cellular responses to many axon guidance cues, interactions between activated receptors modulate cell signals and adhesion. Ultimately, growth cones control axon outgrowth and pathfinding behaviors by integrating distinct biochemical signals to promote the proper assembly of the nervous system. In this review, we discuss our current understanding how ECM proteins and their associated integrin receptors control neural network formation.

The extracellular matrix proteoglycan perlecan facilitates transmembrane semaphorin-mediated repulsive guidance

“…The ECM includes collagens, glycoproteins, and proteoglycans that are produced by developing neurons and glia (Myers et al 2011). Proteoglycans include versican, aggrecan, neurocan, and perlecan (Milev et al 1998); however, with the exception of versican, our understanding of their in vivo axon guidance functions is incomplete (Dutt et al 2011).…”

“…Since guidance cue-directed axon pathfinding likely includes regulation of integrin-based adhesion (Myers et al 2011), cross-talk between semaphorin and integrin signaling has the potential to result in inhibition of integrin-mediated adhesion to the ECM, and vice versa (Serini et al 2003;Oinuma et al 2006;Tran et al 2007).…”

“…Detailed anatomical studies show that growth cones make direct contact with the ECM in vivo (Roberts and Taylor 1982), and ECM ligands and their receptors, such as laminins and integrins, respectively, regulate axon pathfinding in vivo (García-Alonso et al 1996;Hoang and Chiba 1998;Myers et al 2011).…”

Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding

“…For example, NGF, a signal known to promote sympathetic innervation of the islet (Edwards et al, 1989), may be produced by endothelial cells (Cabrera-Vásquez et al, 2009;Gibran et al, 2003;Tanaka et al, 2004). Alternatively, the ability of a neuron to extend a process over a biological substrate requires a direct interaction with the ECM or basal lamina (Myers et al, 2011).…”

The Intracellular Domain of Teneurin-1 Induces the Activity of Microphthalmia-associated Transcription Factor (MITF) by Binding to Transcriptional Repressor HINT1

“…Interestingly, GPNMB also contains an RGD sequence in its ECD, which is likely to bind integrins (45). Integrins have also been studied in the context of axon guidance and neuronal connectivity (48). This leaves us with several potential functions of the teneurin-1 ICD regulating GPNMB expression.…”