The submandibular gland performs important exocrine and endocrine functions and play vital roles in oral and systemic health. Little is known about the molecular genetic basis of its development. The long-term goal has been to determine the role of the first N-glycosylation gene ALG7 in the SMG developmental program. ALG7 is a regulator of lipid-linked oligosaccharide abundance and protein N-glycosylation, and it affects expression of genes that regulate cell proliferation, polarity and differentiation. ALG7 is progressively down-regulated with SMG development, suggesting that attenuation of protein N-glycosylation is required for salivary cell differentiation. Evidence suggests that the high level of ALG7 expression early in SMG embryonic morphogenesis is attained by a transient production of a hyperactive GlcNac P-transferase isoform that disappears as SMG undergoes embryonic cytodifferentiation. One down stream target of ALG7 likely to play key roles in SMG organogenesis is E-cadherin. During early morphogenesis, highly N-glycosylated E-cadherin is found in transient, unstable cell-cell contacts. In contrast, E-cadherin present in stable cell-cell junctional complexes in the cytodifferentiated SMG is hypo-N-glycosylated. The working hypothesis is that by controlling N-glycosylation of E-cadherin, ALG7 regulates the formation of either weak or stable E-cadherin-mediated cell-cell contacts and thus controls SMG morphogenesis and differentiation. To validate the hypothesis, integrated cell biological, molecular, and genetic approaches will be used in four Specific Aims: 1) to establish the roles of GPT isoforms during development; 2) to characterize ALG7-mediated N-glycosylation of E-cadherin during SMG development; 3) to test the hypothesis that changes in E-cadherin N-glycosylation affect the composition of E-cadherin/catenin complexes and their association with the actin cytoskeleton; and 4) to develop mouse models for inappropriate expression of ALG7 in the SMG. The proposed studies will provide new insights into how ALG7 and N-glycosylation regulate salivary gland organogenesis. ? ?
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