Jag2‐Notch1 signaling regulates oral epithelial differentiation and palate development

Abstract

During mammalian palatogenesis, palatal shelves initially grow vertically from the medial sides of the paired maxillary processes flanking the developing tongue and subsequently elevate and fuse with each other above the tongue to form the intact secondary palate. Pathological palate-mandible or palate-tongue fusions have been reported in humans and other mammals, but the molecular and cellular mechanisms that prevent such aberrant adhesions during normal palate development are unknown. We previously reported that mice deficient in Jag2, which encodes a cell surface ligand for the Notch family receptors, have cleft palate associated with palate-tongue fusions. In this report, we show that Jag2 is expressed throughout the oral epithelium and is required for Notch1 activation during oral epithelial differentiation. We show that Notch1 is normally highly activated in the differentiating oral periderm cells covering the developing tongue and the lateral oral surfaces of the mandibular and maxillary processes during palate development. Oral periderm activation of Notch1 is significantly attenuated during palate development in the Jag2 mutants. Further molecular and ultrastructural analyses indicate that oral epithelial organization and periderm differentiation are disrupted in the Jag2 mutants. Moreover, we show that the Jag2 mutant tongue fused to wild-type palatal shelves in recombinant explant cultures. These data indicate that Jag2-Notch1 signaling is spatiotemporally regulated in the oral epithelia during palate development to prevent premature palatal shelf adhesion to other oral tissues and to facilitate normal adhesion between the elevated palatal shelves.

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

“…1B). At the earliest stages examined, headskin and VT consisted largely of a single layer of basal cells, whereas DT and BG epithelia were already two to three cell layers thick, in agreement with previous reports (Baratz and Farbman, 1975;Casey et al, 2006). Growth kinetics varied across tissue types, with DT and BG epithelia stratifying most rapidly and VT more slowly.…”

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

“…Jag1 +/− and Jag2 +/− mice were obtained from the Jackson Laboratory. Genotypes were confirmed by PCR (32)(33)(34), and experiments were performed with generations F4-F6. Littermates were used as wild-type controls.…”

Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development

“…Disruption of the Notch ligand jagged 2 (Jag2) caused cleft palate in Jag2 DSL/DSL mice as a result of aberrant adhesion of the palatal shelves to the tongue (Jiang et al, 1998). Jag2 is expressed throughout the oral epithelium and is required for the maintenance of periderm cells (Casey et al, 2006), which are flattened epithelial surface cells that have been proposed to regulate fusion competence (Fitchett and Hay, 1989). Palate-tongue fusion, albeit less severe, also occurs in Fgf10 -/-embryos, and Jag2 expression was reduced in the mutant palatal epithelium, suggesting that Fgf10 signaling acts upstream of Jag2-Notch signaling to regulate palatal epithelial differentiation .…”