Deposition and role of thrombospondin in the histogenesis of the cerebellar cortex.

Abstract

Abstract. The patterns of deposition of thrombospondin (TSP), a trimeric extracellular matrix glycoprotein, were determined during the initial establishment of the external granule cell layer and the subsequent inward migration of granule cells forming the molecular and (internal) granule cell layers. The early homogeneous deposition of TSP became restricted to the rhombic lip in the region of granule cell exit from the neuroepithelium, and was present between migrating granule cells.During the later inward migration of granule cells, little TSP was associated with dividing granule cells; it was enriched in premigratory granule cells. With the cessation of migration, TSP was lost except in association with fasciculating axons in the molecular layer where staining persisted briefly. At the EM level, TSP was associated with the leading process of granule cells as they associated with Bergmann glial cells and migrated through the molecular layer. TSP was present within granule cell axons; Purkinje cells and their dendrites, as well as Bergmann glial fibers and endfeet were negative for TSP.When anti-TSP antibodies were added to explant cultures of cerebellar cortex during active granule cell migration, a dose-dependent inhibition of migration was observed. In control cultures, granule cells migrated into the (internal) granule cell layer, while granule cells exposed to anti-TSP antibodies were arrested within the external granule cell layer. These resuits suggest that TSP plays an important role in the histogenesis of the cerebellar cortex by influencing granule cell migration.

Extracellular Matrix Molecules And Their Receptors: Functions In Neural Development

“…Both observations suggest that tenascin functions as an important substrate for granule cell migration. Thrombospondin is associated with granule cells in the premigratory zone of the external granule cell layer and in the molecular layer (O'Shea et al 1990). In contrast to tenascin, thrombospondin is not associated with the surfaces of the Bergmann glia, but is instead concentrated at the leading edges of the migrating granule cells.…”

“…During postnatal development, cerebellar granule cells proliferate in the external granule cell layer and then migrate through the molecular layer to reach their final positions in the internal granule cell layer. Several ECM components and CAMs have been identified in the developing cerebellar cortex, including tenascin (cytotactin), thrombospondin, chondroitin sulfate proteoglycan, hyaluronic acid, and L1 (Hoffman et al 1988, Chuong et al 1987, O'Shea et al 1990, Ripellino et al 1989. Perturbation experiments implicate several of these molecules in granule cell development.…”

“…Thrombospondin antibodies prevent the migration of granule cells into the molecular layer. Although thrombospondin may stimulate migration as a substrate, its ability to bind and activate plasminogen and tissue plasminogen activator (Silverstein et al 1986) suggests that it may function instead by localizing and activating proteases released by the granule cells (Verrall & Seeds 1989, O'Shea et al 1990. Consistent with this idea, inhibitors of the tissue plasminogen activator/plasminogen system can also inhibit cerebellar granule cell migration from the external granule cell layer into the molecular layer (Moonen et al 1982).…”

Thrombospondin-1 Induces Tyrosine Phosphorylation of Adherens Junction Proteins and Regulates an Endothelial Paracellular Pathway

“…Understanding the mechanism(s) through which TSP influences homotypic EC-EC adhesion as well as EC shape changes and migration has implications for vasculogenesis, tissue morphogenesis, and fetal development (O'Shea et al, 1990;O'Shea and Dixit, 1998), as well as angiogenesis (Taraboletti et al, 1990;Iruela-Arispe et al, 1991), within the context of wound healing (Munjal et al, 1990;DiPietro et al, 1996), tissue remodeling (Botney et al, 1992;Kuhn and Mason, 1995), and tumor cell survival (Roberts, 1996). TSP also promotes leukocyte and tumor cell motility in vitro (Taraboletti et al, 1987;Mansfield et al, 1990) and modulates tumor cell adhesion to ECs (Incardona et al, 1995).…”

Substance P responsiveness of smooth muscle cells is regulated by the integrin ligand, thrombospondin.

“…The possibility that TSP may influence the regulation of substance P responsiveness in other pharmacologically versatile cells like vascular smooth muscle and neurons needs examination, as this molecule is synthesized and secreted by vascular endothelial cells (48)(49)(50) and is widespread in brain (51,52). In addition to an influence on substance P responsiveness, an examination of the influence of TSP(s) on expression of the neuropeptide, substance P, is of interest, because ECM-associated components are in an ideal position to interact with both pre-and postsynaptic cells.…”