(which binds the pro-domain of proNTs) causes a p75NTR-dependent signal transduction cascade. The cleaved death domain of p75NTR activates c-Jun N-terminal kinase (JNK). The activated JNK translocates into the nucleus, where it phosphorylates and transactivates c-Jun. The transactivation of c-Jun results in the transcription of pro-apoptotic factors TFF-a, Fas-L and Bak. The importance of sortilin in p75NTR-mediated apoptosis is exhibited by the fact that the inhibition of sortilin expression in neurons expressing p75NTR suppresses proNGF-mediated apoptosis, and the prevention of proBDNF binding to p75NTR and sortilin abolished apoptotic action. Activation of p75NTR-mediated apoptosis is much more effective in the absence of Trk receptors due to the fact that activated Trk receptors suppress the JNK cascade. The expression of TrkA or TrkC receptors in the absence of neurotrophins can lead to apoptosis, but the mechanism is poorly understood. The addition of NGF (for TrkA) or NT-3 (for TrkC) prevents this apoptosis. For this reason TrkA and TrkC are referred to as dependence receptors, because whether they induce apoptosis or survival is dependent on the presence of neurotrophins. The expression of TrkB, which is found mainly in the CNS, does not cause apoptosis. This is thought to be because it is differentially located in the cell membrane while TrkA and TrkC are co-localized with p75NTR in lipid rafts. In the PNS (where NGF, NT-3 and NT-4 are mainly secreted) cell fate is determined by a single growth factor (i.e. neurotrophins). However, in the CNS (where BDNF is mainly secreted in the spinal cord, substantia nigra, amygdala, hypothalamus, cerebellum, hippocampus and cortex) more factors determine cell fate, including neural activity and neurotransmitter input. Neurotrophins in the CNS have also been shown to play a more important role in neural cell differentiation and function rather than survival. For these reasons, compared to neurons in the PNS, neurons of the CNS are less sensitive to the absence of a single neurotrophin or neurotrophin receptor during development; with the exception being neurons in the thalamus and substantia nigra. Gene knockout experiments were conducted to identify the neuronal populations in both the PNS and CNS that were affected by the loss of different neurotrophins during development and the extent to which these populations were affected. These knockout experiments resulted in the loss of several neuron populations including the retina, cholinergic brainstem and the spinal cord. It was found that NGF-knockout mice had losses of a majority of