Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR
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ABSTRACT Animals lacking neurotrophin-3 (NT-3) are born with deficits in almost all sensory ganglia. Among these, the trigeminal ganglion is missing 70% of the normal number of neurons, a deficit which develops during the major period of neurogenesis between embryonic stages (E) 10.5 and E13.5. In order to identify the mechanisms for this deficit, we used antisera specific for TrkA, TrkB, and TrkC to characterize and compare the expression patterns of each Trk receptor in trigeminal ganglia of wild type and NT-3 mutants between E10.5 and E15.5. Strikingly, TrkA, TrkB, and TrkC proteins appear to be exclusively associated with neurons, not precursors. While some neurons show limited co-expression of Trk receptors at E11.5, by E13.5 each neuron expresses only one Trk receptor. Neuronal birth dating and cell counts show that in wild-type animals all TrkB- and TrkC-expressing neurons are generated before E11.5, while the majority of TrkA-expressing neurons are generated between E11.5 and E13.5. In mice lacking NT-3, the initial formation of the ganglion, as assessed at E10.5, is similar to that in wild-type animals. At E11.5, however, the number of TrkC-expressing neurons is dramatically reduced and the number of TrkC-immunopositive apoptotic profiles is markedly elevated. By E13.5, TrkC-expressing neurons are virtually eliminated. At E11.5, compared to wild type, the number of TrkB-expressing neurons is also reduced and the number of TrkB immunoreactive apoptotic profiles is increased. TrkA neurons are also reduced in the NT-3 mutants, but the major deficit develops between E12.5 and E13.5 when elevated numbers of TrkA-immunoreactive apoptotic profiles are detected. Normal numbers of TrkA- and TrkB-expressing neurons are seen in a TrkC-deficient mutant. Therefore, our data provide evidence that NT-3 supports the survival of TrkA-, TrkB- and TrkC-expressing neurons in the trigeminal ganglion by activating directly each of these receptors in vivo.
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Neurotrophins play very important roles in the development and maintenance of the vertebrate nervous system. In mammals, there are four members of the family: NGF, BDNF, NT-3, and NT-4/5. Members of the neurotrophin family activate different receptors that belong to a class of receptor tyrosine kinases known as “Trks.” For example, NGF is the specific ligand of TrkA, while BDNF activates TrkB. To elucidate which regions of the two neurotrophins determine the receptor specificities, chimeric neurotrophins were constructed using BDNF as the backbone, with various regions being substituted by the corresponding regions of NGF. The activity of the chimeras on the Trk receptors was assayed in transfected fibroblasts ectopically expressing the Trk receptors. Our findings revealed that, although BDNF is absolutely conserved in mammals, substitution of several small variable regions from NGF into the BDNF backbone did not lead to significant loss in TrkB activity or gain in TrkA activity. Moreover, important determinants of TrkB activation might be located in the carboxy-terminal half of BDNF. On the other hand, critical elements for TrkA activation might be located within the amino-terminal half of the mature NGF molecule. © 1996 Wiley-Liss, Inc.
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