The elucidation of the mechanisms of cell migration during central nervous system (CNS) development is important to number of issues in neurobiology. Although the phenomenon of neuronal cell migration has been appreciated for more than a century, identification of The molecular components regulating neuronal cell migration is only beginning to emerge. While neurogenesis occurs in a systematic laminar progression, the mechanisms underlying glial cell dispersion within the CNS are not well understood, and the molecules involved in glial cell migration are yet to be elucidated. In the last several years, our appreciation of the extracellular matrix (ECM) of the CNS has grown. The brain ECM consists of a heterogeneous mixture of glycoconjugates, including the glycosaminoglycan hyaluronan (HA). HA regulates the local cellular environment by facilitating permeability and retention of low molecular weight solutes, while excluding other macromolecules. In a number of systems, including the developing CNS, HA has been implicated in cell and tissue specific functions, including the regulation of cell proliferation, differentiation and migration. HA is the only glycosaminoglycan not covalently associated with core protein; therefore, functions ascribed to HA are likely mediated by proteins which bind HA. We recently identified the gene for a new ECM protein, BEHAB (Brain Enriched HyAluronan-Binding). BEHAB represents the only tissue specific HA-binding protein reported to date. BEHAB mRNA expression is restricted to the CNS. BEHAB mRNA is expressed at high levels when astrocytes proliferate and migrate - during rat brain development, in the reactive gliosis induced by CNS injury and during glioma invasion. These observations have led to the hypothesis we propose to test: that the expression of BEHAB plays a role in regulating astrocyte differentiation and motility in the CNS. Thus far, we have characterized the expression of the BEHAB gene at the mRNA level. The BEHAB cDNA encodes putative secretedHA-binding protein. To ascertain the function of BEHAB, it will be necessary to determine the expression pattern of the extracellular protein product of the BEHAB gene. The first specific aim of this project is to characterize th distribution and regulation of the BEHAB protein during CNS development. BEHAB mRNA is expressed in primary rat astrocyte cultures. However, different levels of BEHAB are expressed by astrocytes derived from different brain areas and from different developmental stages. The second specific aim of this project is to determine how BEHAB expression is regulated. BEHAB mRNA is expressed at high levels during periods of astrocyte cell differentiation and migration. The third specific aim of this project is to test whether BEHAB plays a role in astrocyte differentiation and migration.
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