Researchers Study Salivary Gland Development

Da Vinci’s Rule pertains to the ratios of branch diameters in bifurcating trees. The rule goes like this: D1:D2 = D2:D3. Translation: The thickness of a tree branch equals the sum of the branch thickness at any higher level. For biologists, Da Vinci’s Rule and mathematical models in general have been extremely useful as starting points to correlate the actions of key molecules that orchestrate the tree-like branching patterns of developing tissue in organs such as the lungs, kidneys, and salivary glands. The problem is the models are limited in their ability to drill down even deeper into cells and track the integrated energy flow of the subcircuits that sequentially turn on and off to control the complex, 3-dimensional branching of forming epithelial tissue, a process called branching morphogenesis. From the perspective of the emerging field of systems biology, a “subcircuit” is a distinct signaling unit hardwired into the larger, metaphorical circuit board that is a cell. An individual subcircuit consists of several protein signaling pathways that synchronize their actions to control a specific subtask, such as branching morphogenesis, within a developing organ. 

In the June issue of the journal BMC Developmental Biology, National Institute of Dental and Craniofacial Research (NIDCR) grantees drill down deeper into the developing submandibular salivary gland, or SMG, in mice to take a fascinating look at the signaling dynamics of a 5-pathway subcircuit involved in branching morphogenesis. In their study, the scientists compared the developing SMG in normal mice with those of the Tabby mutant. The latter produces low levels of Ectodysplasin-A, or Eda, a key driver of epithelial tissue differentiation during branching morphogenesis. The comparison allowed a quantitative exploration into how a marked reduction in Eda affects in time the broader 5-pathway subcircuit that is critical to the formation of the SMG and which share post-activation protein targets. Interestingly, this more-informative, quantitative in vivo approach refuted the group’s previous conclusions based on their work in vitro. Those studies had suggested that Eda signaling largely regulated SMG development through the canonical Nuclear Factor kappa B regulatory pathway. Their latest data show that not to be the case in the Tabby mouse, and indicated dramatically altered expression involving a downstream subset of genes. “When a gene that is critical to [in this case, Eda to branching morphogenesis] mutates, the differentiating cells reprogram transcription via a cognate genetic circuit, ultimately altering the expression of the many genes beyond the mutated one,” the study authors concluded. “As such, the phenotype of the genotype cannot be simply predicted by the sum of its single locus effects, but must take account of the almost certain epistasis in gene function. The most efficient way of doing this is by systems analysis, correlation modeling for hypothesis generation and kinetic (mechanistic) modeling for hypothesis testing.”