Function and evolution in the NGF family and its receptors

The gene family of neurotrophins includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Recently, neurotrophin-5 (NT-5), a possible mammalian homologue to NT-4 described in the frog Xenopus, has been cloned in man and rat. The neurotrophins stimulate survival and differentiation of a range of target neurons by binding to cell surface receptors. The structure of NGF has recently been clarified from crystallographic data. The similarities between the different neurotrophins are substantial with the variable regions, giving specificity to each of the family members, being localized to some exposed loop regions. Low-affinity binding (Kd of 10(-9) M) of all tested neurotrophins is mediated via a 75 K glycoprotein (LNGFR) that has been cloned and characterized. A 140 K tyrosine protein kinase encoded by the proto-oncogene trk has been found to bind NGF with high affinity (Kd of 10(-11) M) and to evoke the cellular neurotrophic responses. In addition, a protein encoded by the trk-related gene trkB has been shown to bind BDNF. Recently, a third member of the trk family, trkC, has been cloned and demonstrated to function as a high-affinity receptor for NT-3. The expression of trk and LNGFR mRNA are co-localized in the rat brain to the medial septal nucleus and the nucleus of Broca's diagonal band containing the NGF-responsive magnocellular cholinergic neurons projecting to hippocampus and cerebral cortex. In sharp contrast, the pattern of expression of trkB is widely spread in many areas of the cortex as well as lateral septum. The trkB protein might serve general functions in large areas of the cortex. Site-directed mutagenesis and expression of recombinant chimaeric neurotrophin proteins have made it possible to localize a likely region for the interaction between NGF and the LNGFR. This region could be altered, resulting in the total loss of LNGFR binding by the mutant NGF protein without affecting the binding to the trk receptor which was sufficient for the full biological activity. Cladistic analysis of likely phylogenies within the neurotrophins shows BDNF and NT-4 to be most closely related whereas NGF may be the sister group to NT-3, BDNF, and NT-4. Neurotrophins offer obvious clinical possibilities for treatment of neurodegenerative diseases.