Antagonistic roles of full-length N-cadherin and its soluble BMP cleavage product in neural crest delamination.
During neural crest ontogeny, an epithelial to mesenchymal transition is necessary for cell emigration from the dorsal neural tube. This process is likely to involve a network of gene activities, which remain largely unexplored. We demonstrate that N-cadherin inhibits the onset of crest delamination both by a cell adhesion-dependent mechanism and by repressing canonical Wnt signaling previously found to be necessary for crest delamination by acting downstream of BMP4. Furthermore, N-cadherin protein, but not mRNA, is normally downregulated along the dorsal tube in association with the onset of crest delamination, and we find that this process is triggered by BMP4. BMP4 stimulates cleavage of N-cadherin into a soluble cytoplasmic fragment via an ADAM10-dependent mechanism. Intriguingly, when overexpressed, the cytoplasmic N-cadherin fragment translocates into the nucleus, stimulates cyclin D1 transcription and crest delamination, while enhancing transcription of beta-catenin. CTF2 also rescues the mesenchymal phenotype of crest cells in ADAM10-inhibited neural primordia. Hence, by promoting its cleavage, BMP4 converts N-cadherin inhibition into an activity that is likely to participate, along with canonical Wnt signaling, in the stimulation of neural crest emigration.
Shoval
Irit
I
Department of Anatomy and Cell Biology, Hebrew University, Hadassah Medical School, Jerusalem, Israel.
Ludwig
Andreas
A
Kalcheim
Chaya
C
D000818:Animals; D030801:Animals, Genetically Modified; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D002453:Cell Cycle; D002465:Cell Movement; D003370:Coturnix / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D008959:Models, Neurological; D009154:Mutation; D009432:Neural Crest / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D051153:Wnt Proteins / Q000378:metabolism; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D015820:Cadherins; D002352:Carrier Proteins; D019938:Cyclin D1; D010446:Peptide Fragments; D051153:Wnt Proteins; D000099176:Noggin Protein