Genetic Regulation of Branching Morphogenesis: Lessons Learned from Loss-of-Function Phenotypes

Abstract

Branching morphogenesis, defined as growth and branching of epithelial tubules during embryogenesis, is a fundamental feature of renal, lung, mammary gland, submandibular gland, and pancreatic morphogenesis in mammals. Disruption of branching morphogenesis has been demonstrated to result in maldevelopment of some of these organs. Genetic studies performed in affected humans and mutant mice have implicated transcription factors, secreted growth factors, and cell surface signaling molecules as critical regulators of branching morphogenesis. These factors function within networks that appear to exert tight control over the number and location of branches. This review summarizes current knowledge regarding the molecular control of branching morphogenesis in vivo with particular emphasis on the genetic contribution to perturbed branching morphogenesis in mice and humans. OVERVIEWBranching morphogenesis, defined as growth and branching of epithelial tubules during embryogenesis, is fundamental to the formation of several mammalian tissues including the kidney, lung, salivary gland, mammary gland, and pancreas. During branching morphogenesis, a treelike (e.g. kidney) or bushlike (e.g. salivary gland) tubular network is generated via mesenchymal-epithelial tissue interactions mediated, in part, by the coordinated actions of a complex network of gene products. The expression pattern of a large number and variety of genes has been demonstrated in branching organs. Although the structural and functional properties of many of these gene products, defined in in vitro systems, suggest that they may serve important roles during branching morphogenesis, a

Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ

“…However, there are similarities in the embryonic development of the kidney and lung. Both involve common processes, e.g., branching morphogenesis and common signaling pathways such as sonic hedgehog, fibroblast growth factor, and bone morphogenetic protein (17,41). These similarities raise the possibility that TAZ may be an effector in a common pathway that is involved in both lung and kidney development.…”

Interstitial cells of Cajal in pancreas

“…From the developmental point of view, the presence of ICC in pancreatic interstitium may be sustained by recent advances in understanding pancreatic morphogenesis [52][53][54] (the common embryological origin of gastrointestinal tube and pancreas). It was shown that the Sonic Hedgehog (Shh) cell-signaling pathway may direct mesoderm differentiation in the intestine and/or pancreas [55,56].…”

Network rewiring is an important mechanism of gene essentiality change

“…Consequently, the deletion of Map2k1 is not lethal in yeast, but causes embryonic lethality in mice23. Among the interaction partners of Map2k1 is epidermal growth factor receptor, EGFR , which regulates the epidermal growth factor pathway that is crucial for cell growth and morphogenesis16.…”