Neurotrophins, such as nerve growth factor (NGF), can interact with two classes of receptors: the receptor tyrosine kinases Trk receptors or the death-domain receptor p75NTR. Binding to the Trk receptors mediates cell survival signals and is also important for cell development and differentiation. Activation of the p75NTR receptor initiates an apoptotic signal and can lead to cell death. Majdan et al. used a genetic approach to determine whether interactions between the p75NTR and Trk receptors or their signaling pathways were essential for p75NTR-mediated cell death. Cell death was diminished in superior cervical ganglia (SCG) from newborn mice deficient for p75NTR (p75NTR –/– ) and cell death was increased in SCG from mice deficient for TrkA (TrkA –/– ). However, neurons from SCG from double-knockout mice (p75NTR –/– , TrkA –/– ) exhibited enhanced survival, suggesting that the p75NTR can mediate a death signal independent of modulation of TrkA receptor signaling. TrkA and TrkC signaling was not enhanced in cells from p75NTR –/– mice. Pharmacological inhibition of Trk signaling did not promote cell death in the p75NTR –/– cells to that seen in the wild-type cells. The data suggest that in developing sympathetic neurons, the p75NTR death signal is not dependent on modulating the Trk-mediated survival signals. M. Majdan, G. S. Walsh, R. Aloyz, F. D. Miller, TrkA mediates developmental sympathetic neuron survival in vivo by silencing an ongoing p75NTR-mediated death signal. J. Cell Biol. 155 , 1275-1285 (2001). [Abstract] [Full Text]