Trends in Neurosciences
ReviewCompartmentalization from the outside: the extracellular matrix and functional microdomains in the brain
Introduction
The extracellular space, which accounts for approximately 20% of the total volume of the mature brain [1], is filled with a highly organized extracellular matrix (ECM). ECM molecules are already present in the developing embryo, where they play important roles in central nervous system (CNS) development. ECM molecules are also decisive players in the adult CNS, where they are present in almost every structure of the brain and spinal cord [2]. There are multiple forms of ECM structures in the CNS. The most conspicuous of these are the chondroitin sulfate-rich perineuronal nets (PNNs; Glossary) that are associated with mature neurons, and a basal lamina-like ECM that is localized at the blood–brain barrier and in neurogenic niches.
Despite the heterogeneity of the ECM throughout the brain and during different developmental stages (Table 1), it serves a rather universal role as an extracellular scaffold and as a barrier for reducing the diffusion of soluble and membrane-associated molecules. The ECM, therefore, contributes to the clustering of signaling molecules in functional microdomains in neurons and glial cells, as reviewed below. Other important functions of the ECM, such as in the regulation of signaling through cell surface receptors, synaptic plasticity, epilepsy and in response to injury, have been discussed elsewhere 3, 4, 5, 6, 7.
Section snippets
The ECM of the neurogenic niche and its function as a diffusion and cell migration barrier
ECM molecules contribute to the migration and differentiation of stem cells in both the embryonic and adult brain. Considerable knowledge has been gathered concerning the influence of ECM constituents on the life cycle of stem cells in the paradigmatic stem cell system that constantly renews interneurons in the adult olfactory bulb of mammals. This stem cell system is localized in the subependymal zone of the lateral ventricles; this zone has been termed the ‘niche’ because it forms a
The ECM and diffusion of soluble molecules outside of the neurogenic niche
The molecular composition and structural integrity of the ECM are important determinants of the diffusion properties of soluble factors in the mature brain beyond the neurogenic niche. Volume transmission is an important mode of long-range information processing that plays a key role in many diverse brain functions such as vigilance, sleep, long-term potentiation (LTP) and memory formation (reviewed by Ref. [43]). The volume transmission of multiple solutes in the interstitial space of the
The ECM and targeting of membrane proteins at synapses
The importance of the ECM for synaptic organization has been comprehensively demonstrated for agrin, a prominent basal lamina component present between pre- and postsynaptic compartments at the neuromuscular junction (NMJ) [49] (Box 1). In contrast to the NMJ, central synapses possess narrow synaptic clefts and lack basal laminae. This observation led to the concept that pre- and postsynaptic transmembrane cell adhesion molecules directly interact to control the formation, differentiation,
The ECM acts as a physical barrier for the lateral diffusion of membrane molecules
Single- or multi-pass transmembrane proteins can move laterally in the membrane; they are confined by intracellular adaptor proteins linked to the cytoskeleton and by components of the ECM. By tracking fluorescently-labeled single AMPARs and by measurements of fluorescence recovery after photobleaching (FRAP), it has become evident that the ECM presents a physical diffusion barrier for AMPARs at postsynaptic sites [67]. Enzymatic removal of the ECM molecule hyaluronic acid by hyaluronidase
Extracellular compartmentalization of axonal proteins
Axons also harbor several highly specialized subcompartments, such as the axon initial segment (AIS), and the juxtaparanode and internode segments of the nodes of Ranvier, which are ensheathed by specific ECM components. The formation of most of these axonal subcompartments is dependent on interactions with other cells (e.g. myelinating glia). However, the AIS is unique in that the recruitment and retention of AIS proteins is mainly specified intrinsically via axonal cytoskeletal and
The ECM and targeting of membrane proteins at astrocytic endfeet
The ECM also controls the polarized localization of ion channels and transporters in astrocytic membranes. Astrocytic processes contact neurons, blood vessels and other astrocytes with a polarized distribution of membrane proteins, a feature that is considered essential for astrocytic function. For example, inwardly rectifying K+ channels (Kir) and aquaporins (AQPs) are enriched in astrocytic endfeet that contact blood vessels, and their expression levels are controlled by the local ECM.
Summary and outlook
The studies highlighted in this review demonstrate the important and varied roles that the ECM plays in the compartmentalization of diffusible molecules, transmembrane proteins and intracellular molecules at various sites important in the CNS, including the neurogenic niche, synaptic sites, axonal microdomains and astrocytic endfeet.
Neural stem cells in the developing CNS and in adulthood depend on their cellular and molecular environments for correct migration, differentiation and integration
Acknowledgments
We thank Tommaso Fellin and Kim Midwood for their comments on the manuscript. We gratefully acknowledge support by the Italian Institute of Technology (A.D.), the Deutsche Forschungsgemeinschaft (C.S. and M.S.), the New Jersey Commission for Spinal Cord Research and Stem Cell Research (M.S.) and the Bundesministerium für Bildung und Forschung (M.S.).
Glossary
- Basal lamina
- a layer of the ECM commonly found at the interfaces between different cell types. At the electron microscopic level, the basal lamina is composed of an electron-dense layer called the lamina densa (composed of type IV collagen) and an electron-lucid layer called the lamina lucida (consisting of laminin, dystroglycan and associated proteins).
- Fluorescence recovery after photobleaching (FRAP) experiments
- in these experiments a flash of light is used to bleach fluorescently labeled
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