The Mechanism of NGF Suggested by the NGF–TrkA-D5 Complex
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Neurotrophin-3
Trk receptor
Trk receptor
Dorsal root ganglion
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Abstract Sensory neuron development and differentiation is dependent on a family of growth factors known as neurotrophins. Neurotrophins modulate neuron development via trk tyrosine kinase receptor proteins trkA, trkB and trkC. To determine how elevated levels of a target‐derived neurotrophin might affect neuronal differentiation, we analysed trk expression in the trigeminal ganglion of transgenic mice that overexpressed nerve growth factor (NGF) in the skin. increased levels of NGF caused a five‐fold increase in neurons expressing trkA mRNA and a two‐fold increase in neurons expressing trkC. In control mice, cell size distributions of neuronal subpopulations expressing each trk mRNA showed the three subpopulations distributed over a narrow, overlapping range. In contrast, cell size distribution in NGF‐transgenic mice was significantly divergent due in large part to hypertrophy of trkA neurons and, to a lesser extent, trkC neurons. In addition, we examined neurons that bound the isolectin B4 from Bandeiraea simplicifolia (BS‐IB4) because most of these neurons do not express any trk receptor in the adult. There was a significant increase in the size of BS‐IB4–positive neurons in transgenic mice; however, there was no increase in their number. These studies indicate that an increased level of target‐derived NGF affects the development of sensory neurons that in the adult express trkA or trkC, as well as neurons that do not express trk receptors.
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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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The neurotrophin growth factors bind and activate two types of cell surface receptors: the tropomyosin receptor kinase (Trk) family and p75. TrkA, TrkB, and TrkC are bound preferentially by nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 (NT3), respectively, to activate neuroprotective signals. The p75 receptors are activated by all neurotrophins, and paradoxically in neurodegenerative disease p75 is upregulated and mediates neurotoxic signals. To test neuroprotection strategies, we engineered NT3 to broadly activate Trk receptors (mutant D) or to reduce p75 binding (mutant RK). We also combined these features in a molecule that activates TrkA, TrkB, and TrkC but has reduced p75 binding (mutant DRK). In neurodegenerative disease mouse models in vivo, the DRK protein is a superior therapeutic agent compared with mutant D, mutant RK, and wild-type neurotrophins and protects a broader range of stressed neurons. This work rationalizes a therapeutic strategy based on the biology of each type of receptor, avoiding activation of p75 toxicity while broadly activating neuroprotection in stressed neuronal populations expressing different Trk receptors. SIGNIFICANCE STATEMENT: The neurotrophins nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 each can activate a tropomyosin receptor kinase (Trk) A, TrkB, or TrkC receptor, respectively, and all can activate a p75 receptor. Trks and p75 mediate opposite signals. We report the engineering of a protein that activates all Trks, combined with low p75 binding, as an effective therapeutic agent in vivo.
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Abstract The biological actions of neurotrophins are mediated by specific neurotrophin receptor tyrosine kinases (Trks). A low‐affinity nerve growth factor (NGF) receptor, p75, appears to modulate sensitivity to neurotrophins in some neuronal populations. It has been recently demonstrated that genes encoding members of the Trk family are expressed in distinct patterns in the dorsal root ganglia DRG; Mu et al. [1993] (J. Neurosci. 13:4029–4041). However, the extent to which different neurotrophin receptor genes are coexpressed by individual DRG neurons is unknown. The question of coexpression is important since the expression of more than one member of the trk family by DRG neurons would suggest the potential for regulation by multiple neurotrophins. To address this question, a combination of isotopic and colorimetric in situ hybridization was performed on rat thoracic DRG using riboprobes specific for trk A, trkB, trkC, and p75. We show here that neurons that express trkA are largely distinct from those that express trkC, although there is a small subpopulation that expresses both of these genes. We also show that there is a distinct population of DRG neurons that expresses trkB and does not coexpress either trkA or trkC. P75 is expressed in almost all neurons that express trkA or trkB, but is coexpress in only 50% of trkC‐expressing neurons. Importantly, p75 is not expressed in DRG neurons independent of trk expression. Finally, a subpopulation of DRG neurons does not express any of the neurotrophin receptor mRNAs. Our results demonstrate that there are distinct populations of DRG neurons that express each member of the neurotrophin receptor tyrosine kinase family. Our findings of extensive colocalization of p75 with trkA and trkB lend support to the idea that p75 is important in mediating the actions of NGF and brain‐derived neurotrophic factor on DRG neurons. Interestingly, however, p75 expression is clearly unimportant for a subpopulation of neurons that require neurotrophin‐3. The fact that p75 is not expressed in the absence of trkA, trkB, or trkC suggests that the function of p75 is closely related to functions of the known neurotrophin receptor tyrosine kinases. Finally, our results suggest that a significant percentage of DRG neurons may be regulated by non‐neurotrophin neuronal growth factors. © 1995 Willy‐Liss, Inc.
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