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Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not

Abstract

Neurons of the peripheral nervous system have long been known to require survival factors to prevent their death during development. But why they selectively become dependent on secretory molecules has remained a mystery, as is the observation that in the central nervous system, most neurons do not show this dependency. Using engineered embryonic stem cells, we show here that the neurotrophin receptors TrkA and TrkC (tropomyosin receptor kinase A and C, also known as Ntrk1 and Ntrk3, respectively) instruct developing neurons to die, both in vitro and in vivo. By contrast, TrkB (also known as Ntrk2), a closely related receptor primarily expressed in the central nervous system, does not. These results indicate that TrkA and TrkC behave as dependence receptors, explaining why developing sympathetic and sensory neurons become trophic-factor-dependent for survival. We suggest that the expansion of the Trk gene family that accompanied the segregation of the peripheral from the central nervous system generated a novel mechanism of cell number control.

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Figure 1: TrkA and TrkC, but not TrkB, cause the death of ES-cell-derived
Figure 2: Visualization of the nervous system by GFP expressed from the Mapt locus.
Figure 3: Neuronal death and Trk expression.
Figure 4: Loss of TrkA protects sympathetic neurons from cell death in vitro.
Figure 5: Loss of TrkA protects sensory neurons from cell death in vivo.
Figure 6: Trk-induced death without kinase activity.

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Acknowledgements

H.L. is supported by an Emmy-Nother fellowship of the DFG. V.N. and Y.-A.B. thank S. Arber, G. Dechant as well as members of our laboratory for discussions and suggestions.

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Contributions

Tetraploid embryos were generated by P.G. and H.L.; J.M.F. initiated the comparison of the Ngf and TrkA mutant embryos; C.R performed the cloning of the HA-tagged Trk cDNAs; ES lines expressing non-tagged Trk cDNAs from the Mapt locus were generated by M.B.; L.Z. made the first observations with the neuronal differentiation of Trk-expressing ES cells. V.N. and Y.-A.B designed and carried out all other experiments. This work was supported by the consortium EuTRACC and the Swiss National Foundation.

Corresponding authors

Correspondence to Vassiliki Nikoletopoulou or Yves-Alain Barde.

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The authors declare no competing financial interests.

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Nikoletopoulou, V., Lickert, H., Frade, J. et al. Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 467, 59–63 (2010). https://doi.org/10.1038/nature09336

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