Extracellular matrix: functions in the nervous system

Abstract

An astonishing number of extracellular matrix glycoproteins are expressed in dynamic patterns in the developing and adult nervous system. Neural stem cells, neurons, and glia express receptors that mediate interactions with specific extracellular matrix molecules. Functional studies in vitro and genetic studies in mice have provided evidence that the extracellular matrix affects virtually all aspects of nervous system development and function. Here we will summarize recent findings that have shed light on the specific functions of defined extracellular matrix molecules on such diverse processes as neural stem cell differentiation, neuronal migration, the formation of axonal tracts, and the maturation and function of synapses in the peripheral and central nervous system.

Figure 1.

ECM molecules in the developing neocortex. (A) Overview of some ECM molecules found in the embryonic neocortex. Laminin (LN) is a major component of the basal lamina (BL) under the pia mater (P) and is also found in the ventricular zone (VZ). Reelin (RLN) is secreted in the marginal zone (MZ) by Cajal-Retzius cells. Chondroitin sulfate proteoglycans (CSPGs) are concentrated in the subplate region above the intermediate zone (IZ). (B) Higher magnification schematic of the boxed region in (A). RGC endfeet interact with ECM molecules in the BL, such as LN and perlecan (PN), through the integrin (ITG) and dystroglycan (DG) receptors. Radial glia and neurons engage in reelin signaling via the ApoER2 (AP) and VLDLR (VL) receptors.

Figure 2.

ECM and myelination. (A) Oligodendroglia differentiate in sequential stages to generate mature oligodendrocytes. Each oligodendrocyte myelinates several CNS axons. Tenascin-C, laminin, and their β1 integrin receptors play roles at different developmental stages, as indicated. (B) Schwann cells myelinate peripheral nerves. Immature Schwann cells sort out axonal bundles to individually myelinate each axon. Laminin regulates all stages of Schwann cell development, whereas dystroglycan and β1 integrin receptors control axonal sorting and myelination. (C) The ECM surrounding nodes of Ranvier may regulate the local concentration of cations and clusters voltage-gated sodium channels, which allow for saltatory electrical conductivity. Several proteoglycans, tenascin-R, laminin and dystroglycan contribute to the formation of nodal matrices. Na_v, voltage-gated channel; Na⁺, sodium cations.

Figure 3.

ECM molecules at the neuromuscular junction. ECM molecules (BL) are required for NMJ development and function. The heparan sulfate proteoglycan agrin binds to its receptor, Lrp4, and regulates postsynaptic NMJ development through the receptor tyrosine kinase, MuSK. Laminins (LN) are required at the NMJ to promote presynaptic differentiation, as well as postsynaptic maturation via integrin (ITG) and α-dystroglycan (DG) receptors. ITG and DG receptors also bind perlecan (PN) in the BL, which recruits collagen Q (ColQ). ColQ can also bind MuSK and is important for AchR clustering and regulation of Ach levels via recruitment of acetylcholinesterase (AchE) to the NMJ.

Figure 4.

ECM changes at CNS synapses. Synapses are embedded into an ECM meshwork (blue) composed of hyaluronan, chondroitin sulfate proteglycans (CSPGs), tenascins, and others. The composition of the ECM changes during development. For example, neurocan, versican V1, and tenascin-C are abundant in the immature CNS, whereas tenascin-R, versican V2, and Bral1 are prominent in the mature CNS. The mature ECM is thought to restrict dendritic spine motility and lateral diffusion of AMPA receptors (AMPAr). Chondroitinase ABC (chABC) digestion of CSPGs can restore juvenile spine dynamics.