Mechanisms of hippocampal astrocyte cell cycle inhibition by nerve growth factor via p75NTR

CRAGNOLINI, ANDREA BEATRIZ; FRIEDMAN, WILMA J

Congreso; Society for Neuroscience Meeting; 2008

The p75NTR is a cell-surface receptor that binds to all members of the neurotrophin family, of which the prototypic member is nerve growth factor (NGF). The p75NTR can mediate different functions depending on cell context. It is widely expressed in neurons during development, but during adulthood is restricted to a few areas in the brain. However, p75NTR is upregulated after injury. Hippocampal astrocytes do not express TrkA, but do express p75NTR both in vivo and in vitro. Until now, its function has not been characterized.p75NTR was shown to retard cell-cycle progression in several tumor cells, including C6 astroglioma cells. We have demonstrated that NGF does not induce death of hippocampal astrocytes as it does in neurons. However, by binding to p75NTR NGF can decrease the number of astrocytes in culture and the proportion of cells in S phase, suggesting a role in inhibiting the proliferation of astrocytes. Entry into, and progression through, the cell cycle depends on the expression levels and activation of cyclin-cyclin-dependent kinase (cdk) complexes. In this study, we have examined the effect of NGF on cell cycle regulators such as, cyclins, cdks and their inhibitors (CKI), as well as the signaling pathways involved during the suppression of cell-cycle progression of hippocampal astrocyte cultures. To investigate whether NGF regulates the availability of cyclins and cdk inhibitors, we examined the expression of cyclins D1 and E, p15INK4B, p16INK4A and p27Kip1 in astrocytes stimulated with either EGF or serum. We also examined whether NGF can modulate the formation of the cyclin D1-Cdk4 complex. Our results suggest that NGF can inhibit the passage through the G1-S transition in the cell cycle not only by decreasing the expression of cyclins and increasing the availability of CKIs, but also by inhibiting the interaction between cyclins and Cdks.