CD81 regulates neuron-induced astrocyte cell-cycle exit

Astrocytes respond to contact with neurons by cell-cycle arrest and complex process formation. In our effort to discover the molecular mechanisms that underlie this phenomenon we have identified a known tetraspanin, CD81, as a critical component of astrocyte responses to neuronal differentiation sig nals. Here we show that CD81 is expressed on the surface of the astrocyte a nd that its expression level can be modulated by contact with neurons. Furt her, using three separate antibodies, 2F7, Eat1, and Eat2, which recognize unique epitopes in the extracellular domains of the CD81 protein, we show t hat there is a unique domain, recognized by Eat1, that is required for astr ocyte cell-cycle withdrawal in response to neurons. This is likely due to c onformational changes in the CD81 molecule, as inclusion of 2F7 actually au gments neuron-induced astrocyte growth arrest. The critical nature of CD81 in normal astrocyte-neuron biology was confirmed by using mice in which CD8 1 had been deleted by homologous recombination. Astrocytes null at the CD81 locus were blind to the proliferative arrest encoded on the neuronal cell surface. Taken together, these data strongly suggest that CD81 is a critica l regulator of neuron-induced astrocytic differentiation.