The extracellular matrix (ECM) of the adult brain is unique in its molecular composition, and while abundant in various types of proteoglycans, it lacks most common ECM proteins, such as collagens and fibronectin, in its parenchyma. Brevican, a member of the lectican family proteoglycans, is one of the most abundant proteoglycans in the adult brain and is localized mainly in perineuronal nets (PNN), a major form of the ECM in the adult brain surrounding neuronal cell bodies. Dr. Yamaguchi's studies revealed that brevican (and also other lecticans) binds tenascin-R, a nervous system-specific ECM protein, through its C-type lectin domain by protein-protein interactions. Interestingly, both tenascin-R and hyaluronan, another ligand for lecticans, have been identified in PNN. These findings have led to the proposal that hyaluronan, lectican, and tenascin-R form a ternary complex (""""""""HLT complex"""""""") in PNN, and that such a ternary complex constitutes the core of the adult brain ECM. This HLT model has substantial physiological and pathophysiological implications. First, it has been suggested that the PNN is functionally involved in the process of synapse elimination which underlies developmental changes of neural plasticity. Because both lecticans and tenascin-R are known to act as repulsive substrates, it is hypothesized that the HLT complex serves as a super-repulsive substrate that prevents excessive synapse formation on mature neurons. Second, the brain ECM has been implicated in the invasive behavior of glioma cells. As the major components of the brain ECM, the HLT matrix may be an important factor that defines the invasiveness of glioma cells. The main goal of this proposal is to determine the roles of the HLT matrix in adult neural function and in glioma invasion, thereby forming a new paradigm for the physiological and pathophysiological roles of the brain ECM. Toward this goal: 1) the ternary interaction of hyaluronan, brevican, and tenascin-R will be characterized; 2) the effect of the brevican-tenascin-R complex on neurite outgrowth and growth cone responses will be determined; 3) the roles of the HLT matrix on synapse formation and elimination in vivo will be identified using Purkinje cell-targeted transgene expression; and 4) the role of hyaluronan in glioma invasion will be determined by genetic manipulation of hyaluronan synthesis using the hyaluronan synthase Has2.
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