Functions of the neurotrophins during nervous system development: What the knockouts are teaching us

Nerve growth factor (NGF) has long occupied a central position in developmental neurobiology because of the many important neuronal functions it has been shown to regulate. Three decades of work assessing the effects of purified NGF and of antibodies that block its biological activity have led to the following idea: NGF regulates the survival of neurons sensitive to its action during a period of naturally occurring (programmed) cell death in embryonic and early postnatal life. During this same time and at later stages, a variety of other developmental processes such as growth of neurites (axons and dendrites) and synthesis of enzymes required for the production of neurotransmitters are also regulated. There are two unique features of the actions of NGF on neurons as opposed to those of growth factors on other types of cells. First, NGF regulates functions of differentiated neurons, i.e., growth as op posed to proliferation. Second, NGF is synthesized at a considerable distance from the cell body by peripheral tissues or other neurons (referred to as targets) that are contacted by axons of the NGF-sensitive neurons. The secreted NGF is thought to have local effects on axons of innervating neurons as well as more general influences on gene expression after it reaches the cell body (soma) via the process of retrograde transport. Although the purpose of this regulation by neuronal targets has not been clearly established, most investigators have favored the view that target-derived NGF matches the number and properties of innervating neurons to the needs of the target tissue(Purveset al., 1988; Oppenheim, lQQl).Theactions of NGF are restricted to a few populations of neurons. However, the generality of the phenomena of programmed cell death in the newous system and neuronal death after target deprivation induced by transection of axons (axotomy) has suggested that most neurons are regulated by growth factors via a target-derived mechanism. Two landmark studies, the purification of brain-derived neurotrophic factor (BDNF) (Barde et al., 1982) and the identification of the frk proto-oncogene (Martin-Zanca et al., 1988) ultimately led to the cloning of genes for novel members of an NGF family of growth factors (neurotrophins) as well as identification of receptor tyrosine kinases that mediate their biological effects (TM, TrkB, TM). The molecular characteristics and ligand-receptor specificities of the neurotrophin and Trk families are outlined in Figure 1. The identification of these molecules has, at last, allowed neurobiologists to test the generality of ideas that were developed on the basis of three decades of work with NGF. Like all good theories, the NGF model is correct for the systems from which it was derived. However, it is now apparent that regulation of neuronal function by the recently identified members of the neurotrophin family is far more complex than envisioned on the basis of work with NGF, particularly for neurons in the central nervous system (CNS). Furthermore, the number of important cellular processes now thought to be regulated is far greater than was previously realized.