title: Developmental regulation of GDNF response and receptor expression in the enteric nervous system.
abstract: The development of the enteric nervous system is dependent upon the actions of glial cell line-derived neurotrophic factor (GDNF) on neural crest-derived precursor cells in the embryonic gut. GDNF treatment of cultured enteric precursor cells leads to an increase in the number of neurons that develop and/or survive. Here we demonstrate that, although GDNF promoted an increase in neuron number at all embryonic ages examined, there was a developmental shift from a mitogenic to a trophic response by the developing enteric neurons. The timing of this shift corresponded to developmental changes in gut expression of GFR alpha-1, a co-receptor in the GDNF-Ret signaling complex. GFR alpha-1 was broadly expressed in the gut at early developmental stages, at which times soluble GFR alpha-1 was released into the medium by cultured gut cells. At later times, GFR alpha-1 became restricted to neural crest-derived cells. GFR alpha-1 could participate in GDNF signaling when expressed in cis on the surface of enteric precursor cells, or as a soluble protein. The GDNF-mediated response was greater when cell surface, compared with soluble, GFR alpha-1 was present, with the maximal response seen the presence of both cis and trans forms of GFR alpha-1. In addition to contributing to GDNF signaling, cell-surface GFR alpha-1 modulated the specificity of interactions between GDNF and soluble GFR alphas. These experiments demonstrate that complex, developmentally regulated, signaling interactions contribute to the GDNF-dependent development of enteric neurons.
authors.affiliation: Department of Molecular Genetics, Biogen, Inc., Cambridge, MA 02142, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Worley
authors.forename: J M
authors.initials: JM
authors.lastname: Pisano
authors.forename: E D
authors.initials: ED
authors.lastname: Choi
authors.forename: L
authors.initials: L
authors.lastname: Walus
authors.forename: C A
authors.initials: CA
authors.lastname: Hession
authors.forename: R L
authors.initials: RL
authors.lastname: Cate
authors.forename: M
authors.initials: M
authors.lastname: Sanicola
authors.forename: S J
authors.initials: SJ
authors.lastname: Birren
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004064:Digestive System / Q000196:embryology; D029721:Drosophila Proteins; D017615:Enteric Nervous System / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D066298:In Vitro Techniques; D008024:Ligands; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009432:Neural Crest / Q000196:embryology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: D029721:Drosophila Proteins; C495041:Gdnf protein, rat; C494989:Gfra1 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C495001:Ret protein, rat