Meckel's cartilage differentiation is dependent on hedgehog signaling.
The hedgehog (Hh) signaling pathway has been shown to be essential for craniofacial development. Although mandibular arch derivatives are largely absent in Shh null mice, little is known about the role of Hh signaling during Meckel's cartilage development per se. Mandible development is dependent on the morphogenesis of Meckel's cartilage, which then serves as a template for subsequent skeletal differentiation. In this study, we examine the biological function of Hh signaling during Meckel's cartilage development in vivo and in vitro. E13.5 Shh null mice present a small mesenchymal condensation in the region of a presumptive Meckel's cartilage in the hypoplastic mandibular arch. By E15.5, the Shh mutant exhibits a mere remnant of the mandibular arch, without evidence of Meckel's cartilage differentiation. Further, wild-type embryonic (E11 or E12) mandibular explants cultured for up to 5 days in the presence of cyclopamine, a steroidal alkaloid that specifically disrupts the Hh signaling pathway, exhibit a stage-dependent inhibition of Meckel's cartilage chondroblast differentiation to mature chondrocytes. This phenotype can be rescued by exogenous FGF8, a downstream effector of Hh signaling. Taken together, our results indicate that the Hh signaling pathway is critical to Meckel's cartilage ontogenesis and the rate of chondrogenesis, but not to initial primordium formation. The reliance on Hh signaling is stage dependent.
Melnick
Michael
M
Laboratory for Developmental Genetics, USC, Los Angeles, CA 90089-0641, USA. mmelnick@usc.edu
Witcher
Daniel
D
Bringas
Pablo
P
Carlsson
Peter
P
Jaskoll
Tina
T
D000818:Animals; D002356:Cartilage / Q000196:embryology / Q000254:growth & development*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D020219:Chondrogenesis / Q000187:drug effects; D005260:Female; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000378:metabolism; D053823:Hedgehog Proteins; D008297:Male; D008334:Mandible / Q000196:embryology*; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D009024:Morphogenesis; D010012:Osteogenesis / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D014704:Veratrum Alkaloids / Q000494:pharmacology
C496457:Fgf8 protein, mouse; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; C000541:cyclopamine