Neurotrophin-3 is required for the survival-differentiation of subsets of developing enteric neurons.
Neurotrophin-3 (NT-3) promotes enteric neuronal development in vitro; nevertheless, an enteric nervous system (ENS) is present in mice lacking NT-3 or TrkC. We thus analyzed the physiological significance of NT-3 in ENS development. Subsets of neurons developing in vitro in response to NT-3 became NT-3 dependent; NT-3 withdrawal led to apoptosis, selectively in TrkC-expressing neurons. Antibodies to NT-3, which blocked the developmental response of enteric crest-derived cells to exogenous NT-3, did not inhibit neuronal development in cultures of isolated crest-derived cells but did so in mixed cultures of crest- and non-neural crest-derived cells; therefore, the endogenous NT-3 that supports enteric neuronal development is probably obtained from noncrest-derived mesenchymal cells. In mature animals, retrograde transport of (125)I-NT-3, injected into the mucosa, labeled neurons in ganglia of the submucosal but not myenteric plexus; injections of (125)I-NT-3 into myenteric ganglia, the tertiary plexus, and muscle, labeled neurons in underlying submucosal and distant myenteric ganglia. The labeling pattern suggests that NT-3-dependent submucosal neurons may be intrinsic primary afferent and/or secretomotor, whereas NT-3-dependent myenteric neurons innervate other myenteric ganglia and/or the longitudinal muscle. Myenteric neurons were increased in number and size in transgenic mice that overexpress NT-3 directed to myenteric ganglia by the promoter for dopamine beta-hydroxylase. The numbers of neurons were regionally reduced in both plexuses in mice lacking NT-3 or TrkC. A neuropoietic cytokine (CNTF) interacted with NT-3 in vitro, and if applied sequentially, compensated for NT-3 withdrawal. These observations indicate that NT-3 is required for the normal development of the ENS.
Chalazonitis
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Department of Anatomy and Cell Biology, Columbia University, New York, New York 10032, USA. ac83@columbia.edu
Pham
T D
TD
Rothman
T P
TP
DiStefano
P S
PS
Bothwell
M
M
Blair-Flynn
J
J
Tessarollo
L
L
Gershon
M D
MD
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D017615:Enteric Nervous System / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009197:Myenteric Plexus / Q000166:cytology / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology / Q000196:embryology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020812:Receptor, trkC / Q000096:biosynthesis
D000906:Antibodies; D020934:Ciliary Neurotrophic Factor; D020933:Neurotrophin 3; D020812:Receptor, trkC