No abstract

The functions of cellular prion protein (PrP C ) are under intense debate and PrP C loss of function has been implicated in the pathology of prion diseases. Neuronal PrP C engagement with stress-inducible protein-1 and laminin (LN) plays a key role in cell survival and differentiation. The present study evaluated whether PrP C expression in astrocytes modulates neuron-glia cross-talk that underlies neuronal survival and differentiation. Astrocytes from wild-type mice promoted a higher level neuritogenesis than astrocytes obtained from PrP C -null animals. Remarkably, neuritogenesis was greatly diminished in co-cultures combining PrP C -null astrocytes and neurons. LN secreted and deposited at the extracellular matrix by wild-type astrocytes presented a fibrillary pattern and was permissive for neuritogenesis. Conversely, LN coming from PrP C -null astrocytes displayed a punctate distribution, and did not support neuronal differentiation. Additionally, secreted soluble factors from PrP C -null astrocytes promoted lower levels of neuronal survival than those secreted by wild-type astrocytes. PrP C and stress-inducible protein-1 were characterized as soluble molecules secreted by astrocytes which participate in neuronal survival. Taken together, these data indicate that PrP C expression in astrocytes is critical for sustaining cellto-cell interactions, the organization of the extracellular matrix, and the secretion of soluble factors, all of which are essential events for neuronal differentiation and survival.

Gliomas are tumors derived from glia or their precursors within the central nervous system. Clinically, gliomas are divided into four grades and the glioblastoma multiforme (GBM), also referred as grade IV astrocytoma, is the most aggressive and the most common glioma in humans. The prognosis for patients with GBM remains dismal, with a median survival of 9-12 months. Despite their striking heterogeneity, common alterations in specific cellular signal transduction pathways occur within most GBMs. Previous work from our group identified the co-chaperone stress-inducible protein 1 (STI1) as a cell surface ligand for cellular prion (PrP(C)), which leads to the activation of several signal transduction pathways, some of which modulate cell survival. In the present work, we used thymidine incorporation assays to investigate the effect of STI1 upon proliferation of the human glioblastoma-derived cell line A172. Here we report that STI1 is secreted by and induces proliferation in tumor cells, an effect that is modulated by the Erk and PI3K pathways, and that, in contrast to glioma cells, STI1 does not induce proliferation of normal glia. In addition, our data suggest the involvement of PrP(C) in STI1-induced proliferation of A172 cells. These results provide initial evidence of a new functional role for STI1 on the physiology of human gliomas, and may lead to the identification of new therapeutic targets in these tumors.