Compartment

Compartmentalization from the outside: the extracellular matrix and functional microdomains in the brain Alexander Dityatev 1 , Constanze I. Seidenbecher 2 and Melitta Schachner 3, 4 1 Department of Neuroscience and Brain Technologies, Italian Institute of Technology, via Morego 30, Genova, 16163 Italy 2 Leibniz-Institut fu ¨ r Neurobiologie, Brennecke str. 6, 39118 Magdeburg, German y 3 Zentrum fu ¨ r Molekulare Neurobiologie Hamburg, Falkenried 94, Hamburg, 20251 Germany 4 Keck Center for Collaborat ive Neuroscience and Department of Cell Biology and Neurosci ence, Rutgers University, Piscata way, NJ 08854, USA The extracel lular matrix (ECM) of the central nervous system is well recognized as a migration and diffusion barrier that allows for the trapping and presentation of gro wth factor s to the ir rec ept ors at the cel l sur face. Recent data highlight the importance of ECM molecules as synap tic and perisynap tic scaffolds that direc t the clustering of neurotransmitter receptors in the postsyn- aptic compartment and that present barriers to reduce the lateral diffusion of membrane proteins away from syna pses. The ECM also contribute s to the migrati on and differentiation of stem cells in the neurogenic niche and organizes the polarized localization of ion channels and transport ers at conta cts between astrocytic pro- cesse s and blood vess els. Thus, the ECM contributes to functional compartmentalization in the brain. Introduction The extracellular space, which accounts for approximately 20 % ofthe total vo lume of the mature br ain [1], is ﬁlle d wi th a highly organized extrac ellular 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 struc tur e of thebrainand spi nal co rd [2]. The re ar e mul ti ple fo rms of ECM str uct ure s in the CNS . The most co nsp ic uous of these are the chondroitin sulfate-rich perineuronal nets (PNNs; Glossar y) that are asso ciat ed with mature neur ons, 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 ser ves a rat her uni ver sal role as an ext rac ell ula r scaffold and as a barrier for reducing the diffusion of soluble and memb rane-associated molec ules. The ECM, therefore, contributes to the clustering of signaling molecules in func- tio nal mic rod oma ins in neurons and gli al cel ls, as reviewed below. Other important functions of the ECM, such as in the regulation of signaling through cell surface receptors, synapt ic pla sti cit y, epi lepsy and in res ponse to inj ury, have been discussed elsewhere [3–7]. 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. Review Glossary Basal lamina: a layer of the ECM commonly found at the interfaces between diff eren t cell types. At the electron micros copic level, the basal lamina is composed of an electron-dense layer called the lamina densa (composed of type IV col lagen) and an ele ctron-l ucid layer called the lamina luc ida (consisting of laminin, dystroglycan and associated proteins). Fluorescence recovery after photobleach ing (FRAP) experiment s : in thes e experime nts a flash of light is used to bleach fluorescently labeled molecu les in the regi on of int er est . If the se molecules are able to di ffuse, the non- photobleached fluorescent molecules will migrate into the region of interest and the fluorescent signal at this area will gradually increase in brightness. The rate of recovery provides information about lateral mobility of molecules. Fractones : fract ones are conspic uous aggre gate s of ECM molecul es in the neurogen ic niche that possess a microscopically highly complex fractal-like structure, hence their name. Fractones display some morphological features of basal laminae. The glycoproteins of fractones are different isoforms of laminin chains, collagen type IV, nidogen and, to a lesser extent in the adult, TNC. Glycosaminoglycans : glycosaminoglycans are long, unbranched polysacchar- ides comprising a repeating disaccharide unit. The repeating unit consists of a hexose (a six-carbon sugar) or a hexuronic acid that is linked to a hexosamine (a six-carbon sugar containing nitrogen). Hyaluronidase: an enzyme that degrades hyaluronic acid. Lecticans: a family of CSPGs, which includes aggrecan, versican, brevican and neurocan. These molecules bind to hyaluronan via their N-terminal domains and to the glycoprotei n TNR via their C-terminal domains. Their interaction with hyaluronan is stabilized by link proteins. TNR forms dimers and trimers that crosslink and stabilize hyaluronan –lectican complexes. Lipid raft s: detergent-in soluble cholesterol- and glycolipi d-enriched microdomains of the cell membrane. Long-term potentiation (LTP) : LTP is a long-lasting enhancement in synaptic transmission. After the initial phase of LTP, i.e. induction, there is a period of stabi liza tion (conso lidat ion), duri ng which LTP becomes invulnerable to disr upti on by diff erent conditio ns, which do not affect naı ¨ve syna pses but reverse LTP when applied immediately after its induction. Neurogen ic niche: this niche is a zone in which stem cells are retained during and after onto gene tic deve lopment to produce new cells in the nervous system. Peri neur onal nets (PNNs) : PNNs are con spi c u ou s aggre gat es of ECM molecules that embed cell bodies and proximal dendrites of many neurons in a mesh-like structure that interdigitate s with synaptic contacts and astrocytic processes. In molecular terms, PNNs form a meshwork of intercon nect ed mol ecul es that contain the glycosamino gly can hyaluronan (also called hyaluronic acid), CSPGs, TNR and link proteins. PNNs develop concomitantly with the maturation of brain circu its. They poss ess a dive rse molecul ar comp osit ion; hyalur onic acid is commonly presen t, but some CSPGs and glycan epitopes are selectively accumulated only in subsets of PNNs. Volume transmission: themodeof sign altransmissionwhichis cha rac teri zedby diffusion of signaling molecules in a three-dimensional fashion within the brain extracellular fluid before they activate or modulate receptors on target cells. Corresponding authors: Ditya tev, A . ( [email protected] ); Schachner, M. ([email protected] ). 0166-2236/$ – see front matter 2010 Elsevier Ltd. All rights reserved. doi: 10.1016/j.tins.2010.08.003 Trends in Neuroscien ces, November 2010, Vol. 33, No. 11 503

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