During development of the nervous system, neuronal populations undergo a process of naturally occurring cell death at the time their axons innervate target areas. It is believed that this process ensures a match between the size of the innervating population and the size of its target territory. The classical neu-rotrophic hypothesis states that production of trophic factors by target organs regulates this matching process. Limited amounts of neurotrophic factors are produced by target cells: neurotrophic factors bind specific receptors, are internalized by projecting neurons, and are transported retrogradely to the soma, where they promote survival.

This hypothesis was first formulated for PNS neurons by Hamburger, Levi-Montalcini, and coworkers (reviews in Levi-Montalcini, 1987; Purves, 1988) on the basis of their landmark experiments with nerve growth factor (NGF), the first neuro-trophic factor discovered: they demonstrated in vivo that this factor is essential for survival of sympathetic and nociceptive sensory neurons. Subsequently, each of the major predictions of the classical neurotrophic hypothesis for NGF was confirmed:

NGF is produced by the nonneuronal targets of sympathetic and sensory neurons but not by the neurons themselves; target ablation or blockage of axonal transport results in the death of neonatal sympathetic and sensory neurons; administration of NGF prevents naturally occurring cell death; NGF binds to specific receptors (trkA) and is retrogradely transported. Now this hypothesis has been extended to the other neurotrophins: brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). The specific receptor for BDNF and NT4 is trkB and for NT3 it is trkC; all neu-rotrophins, NGF included, also bind to p75. It is now clear from examination of mutant mice carrying deletions for the genes encoding neurotrophins and their receptors that specific neuronal populations require trophic support of specific neu-rotrophins from their final targets. A table of neuronal losses in neurotrophin and receptor deficient mice is presented below. For a review on neurotrophic factors and their receptors see Bothwell (1995), Lewin and Barde (1996), and Reichardt and Farinas (1997).

Neuronal Population trkA Deletion

NGF Deletion trkB Deletion

BDNF Deletion

NT4 Deletion trkC Deletion

NT3 Deletion

Sensory Trigeminal

Dorsal root ganglia

Sympathetic Superior cervical ganglion

Nociceptive and thermoceptive neurons missing

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