Nerve growth factor (NGF) was discovered 50 years ago as a molecule that promoted the survival and differentiation of sensory and sympathetic neurons. Its roles in neural development have been characterized extensively, but recent findings point to an unexpected diversity of NGF actions and indicate that developmental effects are only one aspect of the biology of NGF. This article considers expanded roles for NGF that are associated with the dynamically regulated production of NGF and its receptors that begins in development, extends throughout adult life and aging, and involves a surprising variety of neurons, glia, and nonneural cells. Particular attention is given to a growing body of evidence that suggests that among other roles, endogenous NGF signaling subserves neuroprotective and repair functions. The analysis points to many interesting unanswered questions and to the potential for continuing research on NGF to substantially enhance our understanding of the mechanisms and treatment of neurological disorders.

Nerve growth factor signaling, neuroprotection, and neural repair

Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons.

Nerve growth factor plays an important part in neuron-target interactions in the late embryonic and adult brain. We now report that this growth factor controls the proliferation of neuronal precursors in a defined culture system of cells derived from the early embryonic brain. Neuronal precursor cells were identified by expression of the intermediate filament protein nestin. These cells proliferate in response to nerve growth factor but only after they have been exposed to basic fibroblast growth factor. On withdrawal of nerve growth factor, the proliferative cells differentiate into neurons. Thus, in combination with other growth factors, nerve growth factor regulates the proliferation and terminal differentiation of neuroepithelial stem cells.

Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor

Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system.

Neurotrophins have long been known to promote the survival and differentiation of vertebrate neurons. However, these growth factors can also induce cell death through the p75 neurotrophin receptor (p75(NTR)), a member of the tumor necrosis factor receptor superfamily. Consistent with a function in controlling the survival and process formation of neurons, p75(NTR) is mainly expressed during early neuronal development. In the adult, p75(NTR) is re-expressed in various pathological conditions, including epilepsy, axotomy and neurodegeneration. Potentially toxic peptides, including the amyloid beta- (Abeta-) peptide that accumulates in Alzheimer's disease, are ligands for p75(NTR). Recent work also implicates p75(NTR) in the regulation of both synaptic transmission and axonal elongation. It associates with the Nogo receptor, a binding protein for axonal growth inhibitors, and appears to be the transducing subunit of this receptor complex.

Donna Chin

Papers

NGF receptor reexpression and NGF-mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum