Characterization of lecticans in normal brain and glioma: A complex tale of post-translational modification and processing.

다국어 초록 (Multilingual Abstract)

The development of virtually all cells in an organism depends upon interactions with the molecules in their environment. The extracellular matrix (ECM) organizes the extracellular space and plays a critical role in directing these interactions. The central nervous system (CNS) is the most complex tissue in the body, containing a vast variety of cell types, organized in an inordinately specific manner with exquisitely precise connectivity between cells. The assembly of this complex organization requires a heterogeneous and dynamic ECM. Understanding the composition and regulation of the ECM is critical for understanding the development and function of the CNS.
Lecticans, a group of glycoproteins comprised of aggrecan, versican, neurocan, and BEHAB/brevican, are the major hyaluronan-binding chondroitin sulfate proteoglycans (CSPGs) in the ECM of the CNS. Lecticans, through their interactions with HA and a variety of other molecules within the extracellular space, are uniquely positioned to organize the ECM of the CNS. Here we have investigated the role lecticans and post-translational processing of lecticans play in creating the extraordinary diversity of the ECM of the CNS. Previous work with the monoclonal antibodies Cat-301, Cat-315, and Cat-316 showed that these antibodies recognize a remarkably diverse family of HA-binding CSPGs in the ECM of the adult CNS. We show here that all three of these antibodies recognize aggrecan, but differentially glycosylated isoforms of aggrecan. These findings have broad implications for the role that diversity of glycosylation plays in creating unique ECM microenvironments in the CNS. In addition, we examined post-translational modification of another lectican, BEHAB/brevican, in the progression of primary glial tumors in the CNS. While previous work showed that expression of BEHAB/brevican is upregulated in glioma, we show here that it is not just increased expression, but cleavage of the full-length protein that mediates it function in these tumors. Finally, we identified the protease responsible for BEHAB/brevican cleavage as ADAMTS-4. Together these observations indicate that post-translational modifications of lecticans are critical to the function of these molecules and the organization of the ECM of the CNS.