Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity.

Abstract

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.)

Expression of mRNA encoding neurotrophins and neurotrophin receptors in rat thymus, spleen tissue and immunocompetent cells

“…For the rat neurotrophin-3-specific probe, the 0.32-kb EcoRVIScaI fragment of the coding exon was cloned into the pBSKS EcoRV site [12] and was linearized with BamHI. For the neurotrophin-4-specific probe, the 670-bp fragment including the rat neurotrophin-4 coding region was cloned into the pBSKS EcoRI site [9] and was linearized with BstEII. For the TrkA-C probes, the 0.45-bp fragments covering the transmembrane regions and part of the extracellular and intracellular regions were cloned into the pBSKS XhoI site (45) and were linearized with HindIII.…”

Expression of the naturally occurring truncated trkB neurotrophin receptor induces outgrowth of filopodia and processes in neuroblastoma cells

“…In particular, expression of trkA (Martin-Zanca et al, 1989), the signal transducing receptor for nerve growth factor (NGF) (Kaplan et al, 1991a,b;Klein et al, 1991a;Barbacid, 1994) or trkC, the receptor for neurotrophin-3 (NT-3) (Lamballe et al, 1991) is associated with a higher dierentiation stage and more favorable outcome (Nakagawara et al, 1993;Yamashiro et al, 1996). In contrast, expression of trkB (Klein et al, 1989;Middlemas et al, 1991), the receptor for brain-derived neurotrophic factor (BDNF) (Klein et al, 1991b;Soppet et al, 1991;Squinto et al, 1991) and neurotrophin 4/5 (NT-4) (Berkemeier et al, 1991;HallboÈ oÈ k et al, 1991;Ip et al, 1992;Klein et al, 1992) is correlated with N-myc expression and malignant phenotype (Nakagawara et al, 1994). Dierentiation of several human neuroblastoma cells with retinoic acid induces trkB expression Lucarelli et al, 1994Lucarelli et al, , 1995.…”

Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

“…In mammals, these signaling factors include nerve growth factor (NGF; Levi-Montalcini et al 1996), brain-derived neurotrophic factor (BDNF; Leibrock et al 1989), neurotrophin-4 (NT4; Berkemeier et al 1991, Ip et al 1992, and neurotrophin-3 (NT3; Hohn et al 1990, Maisonpierre et al 1990, Rosenthal et al 1990). High-affinity neurotrophin receptors (NTRs) are transmembrane tyrosine kinase receptors that belong to the NTRk proto-oncogene family.…”