Salivary gland branching morphogenesis: a quantitative systems analysis of the Eda/Edar/NFκB paradigm

Abstract

Background: Ectodysplasin-A appears to be a critical component of branching morphogenesis. Mutations in mouse Eda or human EDA are associated with absent or hypoplastic sweat glands, sebaceous glands, lacrimal glands, salivary glands (SMGs), mammary glands and/or nipples, and mucous glands of the bronchial, esophageal and colonic mucosa. In this study, we utilized Eda Ta (Tabby) mutant mice to investigate how a marked reduction in functional Eda propagates with time through a defined genetic subcircuit and to test the proposition that canonical NFκB signaling is sufficient to account for the differential expression of developmentally regulated genes in the context of Eda polymorphism.

Recombinant EDA or Sonic Hedgehog rescue the branching defect in Ectodysplasin A pathway mutant salivary glands in vitro

“…We have sought to build on these data by testing the ability of exogenous Sonic hedgehog (Shh) to rescue Eda pathway mutant SMGs in vitro. We find that supplementation of Edar dlJ/dlJ SMGs with recombinant Shh rescues the observed defects, whereas treatment with recombinant Fgf8, another putative Eda target found to be significantly down-regulated in Eda Ta/Ta SMGs (Melnick et al, 2009), does not rescue the glands.…”

“…Recombinant Shh-N Rescues Branching in Edar dlJ/dlJ SMGs In Vitro qPCR profiling has revealed downregulation of Shh in Eda Ta/Ta SMGs in comparison with WT SMGs (Melnick et al, 2009), and treatment of embryonic Eda Ta/Ta skin cultures with recombinant EDA A1 results in up-regulation of Shh (Pummila et al, 2007). We hypothesized that application of recombinant Shh to Eda pathway mutant SMGs explants would rescue the branching defect.…”

“…In Eda Ta/Ta and Edar dlJ/dlJ adults, the SMGs are hypoplastic with a reduced number of ductal and acinar structures (Blecher et al, 1983;Jaskoll et al, 2003). Regarding the developmental origin of this phenotype, the classical study of gland development in Eda Ta/Ta states that the embryonic SMGs are unaffected (Grü -neberg, 1971), but it has been reported recently that Eda Ta/Ta SMGs exhibit reduced branching and developmental delay from E13 (Melnick et al, 2009). Here, we provide an analysis of Eda Ta/Ta and wild-type (WT) littermate SMGs to build on this data.…”

“…Notably, treatment of embryonic Eda Ta/Ta skin cultures with recombinant EDA A1 results in rapid and significant upregulation of Shh (Pummila et al, 2007). Furthermore, recent quantitative polymerase chain reaction (qPCR) profiling has revealed downregulation of Shh in Eda Ta/Ta SMGs in comparison with WT SMGs (Melnick et al, 2009). We have sought to build on these data by testing the ability of exogenous Sonic hedgehog (Shh) to rescue Eda pathway mutant SMGs in vitro.…”

Salivary Gland Branching Morphogenesis — Recent Progress and Future Opportunities

“…The ability of growth factors to stimulate cell proliferation and to modulate cell motility and migration through complex arrays of interconnected signaling pathways has been extensively characterized and studied in two-dimensional cell culture systems (Alberts et al , 2002). There is increasing knowledge about potentially important signaling pathways in salivary gland development, which are starting to be unified using systems biology approaches (Melnick et al , 2009; Larsen et al , 2010). A major opportunity for the future will be to apply computational modeling to systems biology analyses of specific stages of salivary gland development to provide a more unified, holistic understanding of the complex signaling necessary for efficient gland formation at each phase of development.…”