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Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) are the three members of the neurotrophin family known to exist in mammals. Recently, a fourth neurotrophin (designated neurotrophin-4 or NT-4), which shares all of the features found in the mammalian neurotrophins, has been identified in Xenopus and viper. We used sequences specific to the Xenopus/viiper NT-4 to isolate a neurotrophin from both human and rat genomic DNA that appears to represent the mammalian counterpart of Xenopus/viper NT-4. Human NT-4 as well as a human NT-4 pseudogene colocalize to chromosome 19 band q13.3. Mammalian NT-4 has many unusual features compared to the previously identified neurotrophins and is less conserved evolutionarily than the other neurotrophins. However, mammalian NT-4 displays bioactivity and trk receptor specificity similar to that of Xenopus NT-4.Nerve growth factor (NGF) is the prototypical member of a family of mammalian neuronal survival and differentiation factors (1), known as the neurotrophins, that also includes brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) (2-10). These three neurotrophins are all initially synthesized as larger precursors that are proteolytically cleaved to release the mature neurotrophins. The mature regions of the three neurotrophins display 50-55% amino acid identity to each other, with the major regions of structural similarity bordering six invariant cysteine residues that, in active NGF, have been shown to form three intrachain disulfide bonds.The neurotrophins can be distinguished based on their distinct patterns of spatial and temporal expression (11-15) as well as their differing effects on neuronal targets (3-7). The ability of a cell to respond to a particular neurotrophin appears to be dependent on the presence of the appropriate trk receptor. The three known trk receptors (designated here as trkA, trkB, and trkC) are transmembrane tyrosine protein kinases that specifically bind to the neurotrophins; trkA binds and can be activated by , trkB binds and can mediate functional responses to , and trkC seems relatively specific for .Recently, a fourth neurotrophin (designated neurotrophin-4 or NT-4) has been molecularly cloned from Xenopus (26); a gene segment encoding part of the mature NT-4 from viper was also isolated. Xenopus NT-4 shares all the important features that characterize the mammalian neurotrophins. Here we describe the molecular cloning and characterization of a neurotrophin that apparently corresponds to the mammalian counterpart of Xenopus/viper NT-4. § (The D-number assignment for humNT-4 chromosomal location is D19S202E.)

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