existing neurons, and encourages the growth and differentiation of new neurons and synapses. NT-3 is the third neurotrophic factor to be characterized, after NGF and BDNF. NT-3 is unique among the neurotrophins in the number of neurons it has potential to stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors (TrkC and TrkB). Mice born without the ability to make NT-3 have loss of proprioceptive and subsets of mechanoreceptive sensory neurons. Neurotrophin-4 Neurotrophin-4 (NT-4) is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase. It is also known as NT4, NT5, NTF4, and NT-4/5. DHEA and DHEA sulfate The endogenous steroids dehydroepiandrosterone (DHEA) and its sulfate ester, DHEA sulfate (DHEA-S), have been identified as small-molecule agonists of the TrkA and p75NTR with high affinity (around 5 nM), and hence as so-called "microneurotrophins". DHEA has also been found to bind to the TrkB and TrkC, though while it activated the TrkC, it was unable to activate the TrkB. It has been proposed that DHEA may have been the ancestral ligand of the Trk receptors early on in the evolution of the nervous system, eventually being superseded by the polypeptide neurotrophins. Role in programmed cell death During neuron development neurotrophins play a key role in growth, differentiation, and survival. They also play an important role in the apoptotic programmed cell death (PCD) of neurons. Neurotrophic survival signals in neurons are mediated by the high-affinity binding of neurotrophins to their respective Trk receptor. In turn, a majority of neuronal apoptotic signals are mediated by neurotrophins binding to the p75NTR. The PCD which occurs during brain development is responsible for the loss of a majority of neuroblasts and differentiating neurons. It is necessary because during development there is a massive over production of neurons which must be killed off to attain optimal function. In the development of both the peripheral nervous system (PNS) and the central nervous system (CNS) the p75NTR-neurotrophin binding activates multiple intracellular pathways which are important in regulating apoptosis. Proneurotrophins (proNTs) are neurotrophins which are released as biologically active uncleaved pro-peptides. Unlike mature neurotrophins which bind to the p75NTR with a low affinity, proNTs preferentially bind to the p75NTR with high affinity. The p75NTR contains a death domain on its cytoplasmic tail which when cleaved activates an apoptotic pathway. The binding of a proNT (proNGF or proBDNF) to p75NTR and its sortilin co-receptor