Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system
| Autor: | Li-Chong Wang, Harsha R. Jani, Pascale Durbec, Stavros Taraviras, Maria Grigoriou, Mary Hynes, Vassilis Pachnis, Geoffrey Raisman, Madhu Sukumaran, Camelia V. Marcos-Gutierrez |
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| Předmět: |
medicine.medical_specialty
Glial Cell Line-Derived Neurotrophic Factor Receptors Cell Survival Neurturin Dopamine Gestational Age Mice Transgenic Nerve Tissue Proteins Receptor tyrosine kinase Enteric Nervous System Mice Neurotrophin 3 Neurotrophic factors Mesencephalon Internal medicine Proto-Oncogene Proteins Glial cell line-derived neurotrophic factor medicine Animals Drosophila Proteins Ciliary Neurotrophic Factor Glial Cell Line-Derived Neurotrophic Factor Nerve Growth Factors Neurons Afferent Rats Wistar Molecular Biology Cells Cultured Neurons biology Cell Death Homozygote Proto-Oncogene Proteins c-ret Neural crest Receptor Protein-Tyrosine Kinases Cell Differentiation Embryo Mammalian Cell biology Rats Endocrinology Neural Crest Mutation biology.protein Enteric nervous system GDNF family of ligands Digestive System Developmental Biology Signal Transduction |
| Zdroj: | Europe PubMed Central Scopus-Elsevier |
| Popis: | RET is a member of the receptor tyrosine kinase (RTK) superfamily, which can transduce signalling by glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) in cultured cells. In order to determine whether in addition to being sufficient, RET is also necessary for signalling by these growth factors, we studied the response to GDNF and NTN of primary neuronal cultures (peripheral sensory and central dopaminergic neurons) derived from wild-type and RET-deficient mice. Our experiments show that absence of a functional RET receptor abrogates the biological responses of neuronal cells to both GDNF and NTN. Despite the established role of the RET signal transduction pathway in the development of the mammalian enteric nervous system (ENS), very little is known regarding its cellular mechanism(s) of action. Here, we have studied the effects of GDNF and NTN on cultures of neural crest (NC)-derived cells isolated from the gut of rat embryos. Our findings suggest that GDNF and NTN promote the survival of enteric neurons as well as the survival, proliferation and differentiation of multipotential ENS progenitors present in the gut of E12.5-13.5 rat embryos. However, the effects of these growth factors are stage-specific, since similar ENS cultures established from later stage embryos (E14.5-15.5), show markedly diminished response to GDNF and NTN. To examine whether the in vitro effects of RET activation reflect the in vivo function(s) of this receptor, the extent of programmed cell death was examined in the gut of wild-type and RET-deficient mouse embryos by TUNEL histochemistry. Our experiments show that a subpopulation of enteric NC undergoes apoptotic cell death specifically in the foregut of embryos lacking the RET receptor. We suggest that normal function of the RET RTK is required in vivo during early stages of ENS histogenesis for the survival of undifferentiated enteric NC and their derivatives. |
| Databáze: | OpenAIRE |
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