Salivary gland branching morphogenesis: a quantitative systems analysis of the Eda/Edar/NFkappaB paradigm.
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 EdaTa (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 NFkappaB signaling is sufficient to account for the differential expression of developmentally regulated genes in the context of Eda polymorphism.


RESULTS
The quantitative systems analyses do not support the stated hypothesis. For most NFkappaB-regulated genes, the observed time course of gene expression is nearly unchanged in Tabby (EdaTa) as compared to wildtype mice, as is NFkappaB itself. Importantly, a subset of genes is dramatically differentially expressed in Tabby (Edar, Fgf8, Shh, Egf, Tgfa, Egfr), strongly suggesting the existence of an alternative Eda-mediated transcriptional pathway pivotal for SMG ontogeny. Experimental and in silico investigations have identified C/EBPalpha as a promising candidate.


CONCLUSIONS
In Tabby SMGs, upregulation of the Egf/Tgfalpha/Egfr pathway appears to mitigate the potentially severe abnormal phenotype predicted by the downregulation of Fgf8 and Shh. Others have suggested that the buffering of the phenotypic outcome that is coincident with variant Eda signaling could be a common mechanism that permits viable and diverse phenotypes, normal and abnormal. Our results support this proposition. Further, if branching epithelia use variations of a canonical developmental program, our results are likely applicable to understanding the phenotypes of other branching organs affected by Eda (EDA) mutation.
Melnick
Michael
M
Laboratory for Developmental Genetics, USC, Los Angeles, CA, USA. mmelnick@usc.edu
Phair
Robert D
RD
Lapidot
Smadar A
SA
Jaskoll
Tina
T
D000818:Animals; D053331:Ectodysplasins / Q000235:genetics* / Q000378:metabolism; D053339:Edar Receptor / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D009024:Morphogenesis / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D012469:Salivary Glands / Q000196:embryology* / Q000254:growth & development; D015398:Signal Transduction / Q000235:genetics*
D053331:Ectodysplasins; C506019:Eda protein, mouse; D053339:Edar Receptor; C506009:Edar protein, mouse; D016328:NF-kappa B