The dependence receptor TrkC regulates the number of sensory neurons during DRG development

Developmental biology

Marie Ménard^1¹  Juliana M. Coelho-Aguiar^2²  Clélia Costechareyre^1³ 

[1] Apoptosis, Cancer and Development Laboratory - Equipe labellisée ‘La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France^1;Neuro-Development, Cancer and Signaling, Institut NeuroMyoGène, CNRS UMR 5310, INSERM U1217 de Lyon, UCBL Lyon 1, Faculté de Médecine et de Pharmacie, 8 Avenue Rockfeller, 69008 Lyon, France^3;Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France^2

关键词: Dependence receptor;    Neurotrophin;    Sensory nervous system development;    DRG;    TrkC/NTRK3 mutants;    Proprioceptive neurons;   

DOI  :  10.1016/j.ydbio.2018.07.022

学科分类：生物科学（综合）

来源: Academic Press

【 摘 要 】

The development of the sensory nervous system is the result of fine-tuned waves of neurogenesis and apoptosis which control the appropriate number of precursors and newly generated neurons and orient them toward a specific lineage. Neurotrophins and their tyrosine-kinase receptors (RTK) orchestrate this process. They have long been in the scope of the neurotrophic theory which established that a neuron is committed to die unless a trophic factor generated by its target provides it with a survival signal. The neural death has thus always been described as a "default" program, survival being the major player to control the number of cells. New insights have been brought by the gain of function studies which recently demonstrated that TrkC (NTRK3) is a "dependence receptor" able to actively trigger apoptosis in absence of its ligand NT-3. In order to address the role of TrkC pro-apoptotic activity in the control of sensory neurons number, we generated a TrkC gene-trap mutant mice. We found out that this new murine model recapitulates the sensory phenotype of TrkC constitutive mutants, with reduced DRG size and reduced number of DRG neurons. We engineered these mice strain with a lacZ reporter in order to follow the fate of neurons committed to a TrkC lineage and observed that they are specifically protected from NT-3 mediated apoptosis in NT-3/TrkC double knock-out embryos. Finally, using a chicken model we demonstrated that silencing NT-3 emanating from the ventral neural tube induced apoptosis in the DRG anlage. This apoptosis was inhibited by silencing TrkC. This work thus demonstrates that, during in vivo DRG development, TrkC behaves as a two-sided receptor transducing positive signals of neuronal survival in response to NT-3, but actively inducing neuronal cell death when unbound. This functional duality sets adequate number of neurons committed to a TrkC identity in the forming DRG.

【 授权许可】

CC BY