Biomedical subjects

Yang Chai

Publications and source records attributed to Yang Chai.

23 records · Page 2Linked to original sources

PubMed2003

Developmental expression of Smad1-7 suggests critical function of TGF-beta/BMP signaling in regulating epithelial-mesenchymal interaction during tooth morphogenesis.

Members of the transforming growth factor-beta family (e.g. TGF-beta, BMP and activin) are critical regulators of tooth morphogenesis. The basic TGF-beta signaling engine consists of a receptor complex that activates Smads and a Smad-containing complex that controls transcription of the downstream target genes. Little is known about the expression of endogenous Smads during tooth morphogenesis. Using a cRNA probe or antibody which specifically recognizes the expression of each Smad molecule, we provide a comprehensive endogenous Smad expression analysis during tooth morphogenesis. BMP signaling is transmitted through Smad1 and 5 which are first expressed within the dental lamina and later expand into condensed dental mesenchyme at the bud stage. As tooth development advances into the cap and bell stage, BMP signaling Smads are strongly localized within the inner enamel epithelium (IEE) and cranial neural crest derived dental mesenchyme (DM), indicating their critical role in regulating epithelial-mesenchyme interaction during tooth morphogenesis. Smad2 and 3 are responsible for transmitting TGF-beta/activin signaling and show unique expression patterns during tooth morphogenesis. They are localized within the nuclei of both IEE and DM, suggesting that TGF-beta-activated Smads are critical for regulating tooth development. Smad4, the common Smad, is expressed in both dental epithelium and mesenchyme throughout all stages of tooth morphogenesis. The expression of inhibitory Smads (Smad6 and 7) largely overlaps with receptor regulated Smads, indicating that negative feedback on BMP/TGF-beta signaling is critical throughout all stages of tooth morphogenesis. Our results suggest that both receptor-regulated and inhibitory Smads are important regulators of tooth morphogenesis. The selective activation of Smad, as indicated by nucleartranslocation, may suggest selective activation of different members of the TGF-beta superfamily during tooth development.

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PubMed2002

Receptor-regulated and inhibitory Smads are critical in regulating transforming growth factor beta-mediated Meckel's cartilage development.

The proper development of Meckel's cartilage is critical for craniofacial skeletogenesis, because it serves as the primordium for the formation of mandible, malleus, incus, and sphenomandibular ligament. Cranial neural crest (CNC) cells contribute significantly to the formation of Meckel's cartilage. Members of the transforming growth factor beta (TGF-beta) family control the proliferation and differentiation of CNC cells during craniofacial skeletogenesis. TGF-beta signaling is transduced from the cell membrane to the nucleus by means of specific type I and type II receptors and phosphorylated Smad proteins. Here we demonstrate that application of TGF-beta promotes chondrogenesis by specifically increasing proliferation of CNC-derived chondrocytes and production of extracellular matrix. To understand the molecular regulation of TGF-beta signaling, we have examined the biological function of both TGF-beta receptor-regulated and inhibitory Smads during Meckel's cartilage development. The expression patterns of Smad2, 3, and 7 are identical to the ones of endogenous TGF-beta and its cognate receptors during Meckel's cartilage development, establishing the potential that these intracellular signaling Smads may regulate TGF-beta-mediated chondrogenesis. Functional haploinsufficiency of Smad2 delays TGF-beta-mediated Meckel's cartilage development. Overproduction of Smad7 severely inhibits Meckel's cartilage formation, indicating a negative feedback on TGF-beta signaling by inhibitory Smad is critical in orchestrating TGF-beta-mediated gene regulation during embryonic chondrogenesis. The effectiveness of TGF-beta signaling is highly sensitive to the level of Smad gene expression.

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PubMed2002

Embryonic submandibular gland morphogenesis: stage-specific protein localization of FGFs, BMPs, Pax6 and Pax9 in normal mice and abnormal SMG phenotypes in FgfR2-IIIc(+/Delta), BMP7(-/-) and Pax6(-/-) mice.

Embryonic submandibular salivary gland (SMG) initiation and branching morphogenesis are dependent on cell-cell communications between and within epithelium and mesenchyme. Such communications are typically mediated in other organs (teeth, lung, lacrimal glands) by growth factors in such a way as to translate autocrine, juxtacrine and paracrine signals into specific gene responses regulating cell division and histodifferentiation. Using Wnt1-Cre/R26R transgenic mice, we demonstrate that embryonic SMG mesenchyme is derived exclusively from cranial neural crest. This origin contrasts to that known for tooth mesenchyme, previously shown to be derived from both neural crest and nonneural crest cells. Thus, although both SMGs and teeth are mandibular derivatives, we can expect overlap and differences in the details of their early inductive interactions. In addition, since embryonic SMG branching morphogenesis is analogous to that seen in other branching organs, we also expect similarities of expression regarding those molecules known to be ubiquitous regulators of morphogenesis. In this study, we performed an analysis of the distribution of specific fibroblast growth factors (FGFs), FGF receptors, bone morphogenetic proteins (BMPs) and Pax transcription factors, previously shown to be important for tooth development and/or branching morphogenesis, from the time of initiation of embryonic SMG development until early branching morphogenesis. In addition, we report abnormal SMG phenotypes in FgfR2- IIIc(+/Delta), BMP7(-/-) and Pax6(-/-) mice. Our results, in comparison with functional studies in other systems, suggest that FGF-2/FGFR-1, FGF-8/FGFR-2(IIIc) and FGF-10/FGFR-2(IIIb) signaling have different paracrine and juxtacrine functions during SMG initial bud formation and branching. Finally, our observations of abnormal SMGs in BMP7(-/-) and Pax6(-/-) indicate that both BMP7 and Pax6 play important roles during embryonic SMG branching morphogenesis.

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PubMed2002

Developmental patterning of the circumvallate papilla.

Organogenesis is regulated by the sequential and reciprocal interactions between epithelial and mesenchymal tissues. Many molecules, including growth factors, transcription factors, extracellular matrices, cell surface receptors, and matrix degrading enzymes, have been found to be involved in this process. To investigate the molecular mechanism responsible for morphogenesis of the circumvallate papilla/von Ebners' gland complex, we examined the expression patterns of selected cell adhesion molecules, extracellular matrix molecules, innervation and cell division in the circumvallate papilla of mouse embryos from embryonic day 11.5 (E11.5) to E14. At E11.5-E13.5, the lingual epithelium, the site where the circumvallate papilla will develop, is negative for BrdU labeling. At E14-E15, we detected cell division in the papillary area, especially in the epithelial invagination where von Ebners' minor salivary gland will form. The basement membrane component, laminin, is expressed as a continuous thin line separating the epithelia from the underlying mesenchyme, but it is broadly and strongly expressed in the area wherethe nervefibers penetrate into the circumvallate papilla. At the E12-E12.5 stage of development, the epithelial thickening shows intense E-cadherin staining in the superficial and basal layers, but weak E-cadherin staining in the suprabasal layer. E-cadherin is strongly expressed, but appears dispersed among the basal layer of lingual epithelium, the site where nerve fibers will innervate. At E13, nerve fibers reach the circumvallate papilla. These nerve fibers penetrate into and split the epithelial cell mass into two stalks which will later differentiate to form the von Ebners' gland. These results suggest that 1) the formation of the circumvallate papilla does not initially depend on cell division, 2) cell migration likely plays a major role during circumvallate placode formation, 3) E-cadherin and laminin may play a role in nerve guidance and 4) innervation impacts the final morphogenesis of the circumvallate papilla.

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PubMedDate not supplied

Morphoregulation of teeth: modulating the number, size, shape and differentiation by tuning Bmp activity.

During development and evolution, the morphology of ectodermal organs can be modulated so that an organism can adapt to different environments. We have proposed that morphoregulation can be achieved by simply tilting the balance of molecular activity. We test the principles by analyzing the effects of partial downregulation of Bmp signaling in oral and dental epithelia of the keratin 14-Noggin transgenic mouse. We observed a wide spectrum of tooth phenotypes. The dental formula changed from 1.0.0.3/1.0.0.3 to 1.0.0.2(1)/1.0.0.0. All mandibular and M3 maxillary molars were selectively lost because of the developmental block at the early bud stage. First and second maxillary molars were reduced in size, exhibited altered crown patterns, and failed to form multiple roots. In these mice, incisors were not transformed into molars. Histogenesis and differentiation of ameloblasts and odontoblasts in molars and incisors were abnormal. Lack of enamel caused misocclusion of incisors, leading to deformation and enlargement in size. Therefore, subtle differences in the level, distribution, and timing of signaling molecules can have major morphoregulatory consequences. Modulation of Bmp signaling exemplifies morphoregulation hypothesis: simple alteration of key signaling pathways can be used to transform a prototypical conical-shaped tooth into one with complex morphology. The involvement of related pathways and the implication of morphoregulation in tooth evolution are discussed.

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