Bone morphogenetic protein-2 and -4 limit the number of enteric neurons but promote development of a TrkC-expressing neurotrophin-3-dependent subset.
The hypothesis that BMPs (bone morphogenetic proteins), which act early in gut morphogenesis, also regulate specification and differentiation in the developing enteric nervous system (ENS) was tested. Expression of BMP-2 and BMP-4, BMPR-IA (BMP receptor subunit), BMPR-IB, and BMPR-II, and the BMP antagonists, noggin, gremlin, chordin, and follistatin was found when neurons first appear in the primordial bowel at embryonic day 12 (E12). Agonists, receptors, and antagonists were detected in separated populations of neural crest- and noncrest-derived cells. When applied to immunopurified E12 ENS precursors, BMP-2 and BMP-4 induced nuclear translocation of phosphorylated Smad-1 (Sma and Mad-related protein). The number of neurons developing from these cells was increased by low concentrations and decreased by high concentrations of BMP-2 or BMP-4. BMPs induced the precocious appearance of TrkC-expressing neurons and their dependence on neurotrophin-3 for survival. BMP-4 interacted with glial cell line-derived neurotrophic factor (GDNF) to enhance neuronal development but limited GDNF-driven expansion of the precursor pool. BMPs also promoted development of smooth muscle from mesenchymal cells immunopurified at E12. To determine the physiological significance of these observations, the BMP antagonist noggin was overexpressed in the developing ENS of transgenic mice under the control of the neuron-specific enolase promoter. Neuronal numbers in both enteric plexuses and smooth muscle were increased throughout the postnatal small intestine. These increases were already apparent by E18. In contrast, TrkC-expressing neurons decreased in both plexuses of postnatal noggin-overexpressing animals, again an effect detectable at E18. BMP-2 and/or BMP-4 thus limit the size of the ENS but promote the development of specific subsets of enteric neurons, including those that express TrkC.
Chalazonitis
Alcmène
A
Department of Anatomy and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA. ac83@columbia.edu
D'Autréaux
Fabien
F
Guha
Udayan
U
Pham
Tuan D
TD
Faure
Christophe
C
Chen
Jason J
JJ
Roman
Daniel
D
Kan
Lixin
L
Rothman
Taube P
TP
Kessler
John A
JA
Gershon
Michael D
MD
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins; D002452:Cell Count; D002478:Cells, Cultured; D016207:Cytokines; D004268:DNA-Binding Proteins / Q000378:metabolism; D017615:Enteric Nervous System / Q000166:cytology / Q000378:metabolism*; D005260:Female; D038681:Follistatin / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000196:embryology / Q000294:innervation; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020812:Receptor, trkC / Q000096:biosynthesis*; D017978:Receptors, Growth Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D038681:Follistatin; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020933:Neurotrophin 3; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D012333:RNA, Messenger; D020812:Receptor, trkC; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; C113178:Grem1 protein, mouse; C497401:Smad1 protein, mouse; C497400:Smad1 protein, rat; C054234:chordin; C498212:Bmpr1a protein, mouse; C498213:Bmpr1a protein, rat; C498215:Bmpr1b protein, mouse; C498216:Bmpr1b protein, rat; C498219:Bmpr2 protein, mouse; C498220:Bmpr2 protein, rat