BMP-signaling regulates the generation of hair-cells.
Bone morphogenetic proteins (BMPs) are diffusible molecules involved in a variety of cellular interactions during development. Bmp4 expression accompanies the development of the ear sensory organs during patterning and specification of sensory cell fates, yet there is no understanding of the role of BMP4 in this process. The present work was aimed at exploring the effects of BMP-signaling on the development of hair-cells. For this purpose, we studied gene expression, cell proliferation and cell death in isolated chick otic vesicles that were grown in vitro in the presence of recombinant BMP4 or the BMP-inhibitor Noggin. Cath1 was used as a marker for hair-cell specification. BMP4 reduced the number of Cath1-cells and, conversely, Noggin increased the size of the sensory patches and the number of Cath1-positive cells. The effect of BMP4 was irreversible and occurred before hair-cell specification. Lfng and Fgf10 were expressed in the prosensory domain before Cath1, and their expression was expanded by Noggin. At these stages, modifications of BMP activity did not respecify non-sensory epithelium of the otic vesicle. The expression of Bmp4 at sensory patches was suppressed by BMP4 and induced by Noggin suggesting an autoregulatory loop. Analysis of BrdU incorporation during 6 and 18 h indicated that the effects of BMP4 were due to its ability to reduce the number of actively proliferating progenitors and inhibit cell fate specification. BMP4 induced cell death within the prosensory domain of the otic vesicle, along with the expression of Msx1, but not Msx2. On the contrary, BMP-inhibition with Noggin favored hair-cell specification without changes in the overall cell proliferation. We propose that about the stage of terminal division, the balance between BMP and BMP-inhibitory signals regulates survival and specification of hair-cell precursors, the final number of sensory hair-cells being limited by excess levels of BMPs. The final size of sensory patches would hence depend on the balance between BMP4 and opposing signals.
Pujades
Cristina
C
Biologia del Desenvolupament, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona (PRBB) c/Dr. Aiguader 80, 08003-Barcelona, Spain.
Kamaid
Andrés
A
Alsina
Berta
B
Giraldez
Fernando
F
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D030161:Avian Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002452:Cell Count; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000378:metabolism; D016695:Glycosyltransferases / Q000096:biosynthesis / Q000235:genetics; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000196:embryology* / Q000201:enzymology / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000096:biosynthesis; D009924:Organ Culture Techniques; D009925:Organ of Corti / Q000196:embryology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D000099176:Noggin Protein
D030161:Avian Proteins; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D016695:Glycosyltransferases; D006131:Growth Inhibitors; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; D000099176:Noggin Protein; C084119:MSX2 protein; C498394:LFNG protein, Gallus gallus