Neuronal life and death decisions: functional antagonism between the Trk and p75 neurotrophin receptors

Many developing cell populations depend upon speci®c stimuli for their survival. These stimuli include cell:cell contact, growth factors, cytokines, hormones or electrical activity. For most peripheral nervous system neurons, survival depends upon a family of trophic factors collectively called the neurotrophins, comprised of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophins 3, 4/5, 6 and 7. These growth factors mediate neuronal survival, di€erentiation and growth by interacting with two types of cell-surface receptors, the Trk family of tyrosine kinases and the p75 neurotrophin receptor, a member of a family of receptors that includes fas and TNF receptor. The Trk receptors selectively bind speci®c neurotrophin ligands; NGF binds TrkA, BDNF and NT-4/5 bind TrkB and NT-3 binds TrkC and, with lower anity, TrkA and TrkB. In contrast, all of the mammalian neurotrophins bind to the p75 neurotrophin receptor. Much evidence now indicates that the neurotrophins act through the Trk and p75 neurotrophin receptors to regulate the survival and growth of developing and injured peripheral neurons. In particular, the neurotrophins play a critical role during the period of naturallyoccurring cell death and target innervation, a role ®rst enunciated in the neurotrophic factor hypothesis. In its original form, this hypothesis stated that neuronal growth and survival are regulated by target-derived neurotrophic factors, such as NGF, so that competition for limiting amounts of trophic factors match the number of innervating neurons to target cells. This model was largely based upon work performed with peripheral sympathetic neurons, which are absolutely dependent upon NGF during the period of target competition in vivo. During this developmental window, which occurs neonatally, NGF is believed to bind to its cognate receptors on the terminals of sympathetic neurons and to regulate their level of target innervation via two primary mechanisms. First, NGF stimulates terminal growth of sympathetic neurons thereby regulating the level of target innervation. Secondly, NGF (in conjunction with other neurotrophins, see below) serves as a discriminating mechanism that allows the elimination of neurons that have failed to sequester adequate target territory. Together, these cellular mechanisms ensure appropriate establishment of neuron:target cell interactions. One of the assumptions implicit to the neurotrophic factor hypothesis as it originally developed was that a survival signal mediated by, for example, target-derived NGF was sucient to determine the life or death of a developing neuron. However, recent studies indicate that the survival of developing sympathetic neurons is determined by the balance of target-derived survival versus apoptotic factors and that, surprisingly, these life and death signals are mediated by the neurotrophins, signalling di€erentially via the TrkA and p75 neurotrophin receptors, respectively. These ®ndings raise questions about the mechanisms whereby the neurotrophins mediate neuronal life versus death and the biological rationale for having one class of growth factors Int. J. Devl Neuroscience, Vol. 17, No. 3, pp. 153±161, 1999 # 1999 ISDN. Published by Elsevier Science Ltd All rights reserved. Printed in Great Britain 0736-5748/99 $20.00+0.00