One of the most basic and crucial embryonic processes that develops in virtually all living organisms is the formation of hollow tubular structures of various kinds. These tubes can form blood vessels or a digestive tract and, through branching and differentiation, complex organs including the heart, kidneys, and mammary glands. Abnormalities in these processes can cause congenital disorders such as dysfunctional, displaced, or asymmetric organs, as well as regenerative defects in blood vessels or other regenerative organs.
Despite its fundamental importance, the general mechanisms of hollow tube formation during embryogenesis are not well understood, due to the great diversity of strategies used by animals to form tubular structures.
Enter the starfish, an ancient marine creature whose process of tubulogenesis is relatively easy to study and which is becoming an important organism for understanding the genetics and mechanics of tube formation. In the May 9 issue of nature communicationsMargherita Perillo of the Marine Biological Laboratory (MBL) and collaborators reveal in detail the initiation and early stages of tube formation in starfish homeland miniata.
“Most of our organs are tubular, because they need to transport fluids, gases, food or blood. And more complex organs like the heart start out as a tube and then develop different structures. So tubulogenesis is a very basic step in forming all of our organs,” Perillo said.
Perillo chose the starfish as his research organism “because he wanted to understand the basic mechanism of tube formation that is conserved in all vertebrates. So he needed an animal that would be at the bottom along the tree of life, [evolving] before chordates,” he said.
Using CRISPR and other techniques to analyze gene function, as well as long time-lapse movies of developing sea star larvae, Perillo and his colleagues determined how this organism generates tubes that branch from its gut. Their study defines a basic toolkit from which chordate tubular organs may have developed. (Chordates include vertebrates (fish, amphibians, reptiles, birds, and mammals) and some invertebrate subphyla.)
An open question in biology was exactly how organisms develop from a cell to the complex three-dimensional tubular structures of various organs, Perillo said. In some organisms like flies, “there’s a big round of cell proliferation before all the cells start doing very complex migration patterns to elongate, change shape and become a tube,” he said. In other animals, including mammals, cell proliferation and migration occur together. In the case of the starfish, “I discovered that, for tube formation, cells can proliferate and migrate at the same time,” as they do in developing vertebrates. “So this means that this mechanism of organ creation was already established at the base” or root of chordate evolution, he said.
In addition to providing information about the fundamental process that leads to organ formation, starfish can serve as a model for much biomedical research, Perillo suggests. For example, he discovered that a gene called Six1/2 serves as a key regulator of the branching process in tube formation. In mice, removing Six1/2 causes the kidneys to form abnormally. But researchers have discovered that mice lacking this gene also resist tumor formation, even when injected with tumor cells. The gene, which is overexpressed in cancer cells, could lead to new ways to study disease progression, including cancer.
“Now I can use this gene to understand not only how our organs develop, but also what happens to the organs when we have a disease, especially cancer,” he says. “My hope is that, in a maximum of five to 10 years, we can use this gene to test how organs develop cancer and how cancer becomes metastatic.”
Starfish embryos have many practical experimental advantages, Perillo said. They are mostly transparent, so that internal growth processes can be directly observed over long periods of development without harming the organism. They’re also easy to collect and breed in large numbers year-round, “so I always have plenty of material to work with.”
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