The role of transforming growth factor-beta signalling in the patterning of the proximal processes of the murine dentary

The evolution of the novel mammalian jaw articulation has resulted in an increased complexity of the dentary bone, reflecting the multiple roles it now fulfils as the primary bone of the mandible. Signalling through the Tgf-beta type II receptor is important in the development and patterning of the proximal dentary processes, especially the angular process, and secondary cartilages. We show that expression of Tgf-beta 2 is associated with the developing angular process, and that the connective tissue marker Scleraxis is co-expressed with Tgf-beta 2. Scleraxis expression is lost around the angular process of Tgthr2 conditional knockouts and Tgf-beta signalling can induce Scleraxis expression in explant culture. Induction of secondary cartilages in explant culture can be prevented by inhibition of Tgf-beta signalling. This study suggests that the proper development of the processes and their secondary cartilages relies on both Tgf-beta signalling and mechanical forces working in concer

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

FSP1/S100A4-Expressing Stem/Progenitor Cells Are Essential for Temporomandibular Joint Growth and Homeostasis

The temporomandibular joint (TMJ) is one of the most used joints in the body. Defects and wear in the cartilage of the joint, condyle, and fibrocartilage disc lie at the heart of many common TMJ disorders. During postnatal development, the condyle acts as a growth center for the mandible, with cells moving as a conveyor belt away from the top of the condyle as they differentiate. The superficial layers of the condyle have been proposed to contain stem/progenitor populations to allow growth and maintain homeostasis. Here we have focused on the role of fibroblast-specific protein 1 (FSP1; also known as S100a4) as a key fibroblast stem/progenitor marker for the condyle. Lineage tracing with FSP1-Cre;R26RmTmG mice revealed that FSP1-expressing cells were restricted to the superficial fibroblast zone, giving rise to all layers of the condyle over time. The FSP1-expressing cells overlapped with other putative stem cell markers of the condyle, such as Gli1 and scleraxis. BrdU pulse chase experiments highlighted that a subset of FSP1 fibrocartilage was label retaining, suggesting that FSP1 labels a novel stem/progenitor cell population in the condyle. Destruction of FSP1-expressing cells by conditional diphtheria toxin activity in FSP1-Cre;R26RDTA mice resulted in severe TMJ osteoarthritis with loss of the cartilage structure. Lgr5-expressing cells in the superficial layer of the condyle have been shown to create a Wnt inhibitory niche. FSP1 expression postnatally was associated with a reduction in canonical Wnt activity in the condyle. Importantly, constitutive activation of Wnt/β catenin in FSP1-expressing cells led to a downregulation of FSP1 and progressive postnatal loss of TMJ condylar hyaline cartilage due to loss of the superficial stem/progenitor cells. These data demonstrate a novel role for FSP1-expressing cells in the superficial zone in growth and maintenance of the TMJ condylar cartilage and highlight the importance of regulating Wnt activity in this population. </p

A new developmental mechanism for the separation of the mammalian middle ear ossicles from the jaw

Multiple mammalian lineages independently evolved a definitive mammalian middle ear (DMME) through breakdown of Meckel's cartilage (MC). However, the cellular and molecular drivers of this evolutionary transition remain unknown for most mammal groups. Here, we identify such drivers in the living marsupial opossum Monodelphis domestica, whose MC transformation during development anatomically mirrors the evolutionary transformation observed in fossils. Specifically, we link increases in cellular apoptosis and TGF-BR2 signalling to MC breakdown in opossums. We demonstrate that a simple change in TGF-β signalling is sufficient to inhibit MC breakdown during opossum development, indicating that changes in TGF-β signalling might be key during mammalian evolution. Furthermore, the apoptosis that we observe during opossum MC breakdown does not seemingly occur in mouse, consistent with homoplastic DMME evolution in the marsupial and placental lineages.</p

Synthesis and biological evaluation of some heterocyclic scaffolds based on the multifunctional N

The chloroacetamide derivative, 1, was used as a versatile precursor for the synthesis of various types of N-aryl-2-(benzothiazol-2-ylthio)acetamide derivatives. The reaction of 1 with 2-mercaptobenzothiazole followed by condensation reaction of the produced sulfide with phenylhydrazine, 2-cyanoacetohydrazide, and/or thiosemicarbazide furnished the conforming condensation products, 4, 7, and 10, respectively. Treatment of the phenylhydrazone product, 4, with Vilsmeier formylation reagent (POCl3/DMF) yielded the corresponding 4-formylpyrazole derivative, 5. The thiosemicarbazone product, 10, was reacted with ethyl bromoacetate to furnish the thiazolin-4-one derivative, 11. The substitution reactions of chloroacetamide derivative, 1, with 2-mercapto-4,6-dimethylnicotinonitrile and 6-amino-2-mercaptopyrimidin-4-ol, were explored to identify the sulfide products, 14 and 17. Cyclization of 14 into its corresponding thieno[2,3-b]pyridine compound, 15, was performed using sodium ethoxide. The thiosemicarbazone, 10, and sulfide derivative, 14, were found to be the most potent antibacterial compounds against Escherichia coli and Staphylococcus aureus, exhibiting growth inhibitory activities of 80.8% and 91.7%, respectively. Moreover, the thiosemicarbazone, 10, displayed the most significant antioxidant activity with inhibitory activity of 82.6%, which comes close to the antioxidant activity of L-ascorbic acid