Cellular prion protein expression in astrocytes modulates neuronal survival and differentiation

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 cell-to-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.