One of the most basic and important embryonic processes that appears in almost every living organism is the formation of hollow tubular structures of various types. These tubules may form blood vessels or the 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 asymmetrical organs, as well as regenerative defects in blood vessels or in other regenerative organs.
Despite their fundamental importance, the general mechanisms of hollow tube formation during embryonic development are not well understood, given the wide variety of strategies animals use to form tubular structures.
Enter the starfish, an ancient marine creature whose process of tube formation is relatively easy to study, and which has become an important organism for understanding the genetics and mechanics of tube formation. In the May 9 issue of Nature CommunicationsMargarita Berio of the Marine Biological Laboratory (MBL) and collaborators reveal in detail the initiation and early stages of tube formation in starfish. Patria miniata.
“Most of our organs are tubular, because they need to move liquids, gases, food or blood. More complex organs like the heart start out as a tube and then develop different structures. So tube formation is a very essential step to form all our bodies,” Perillo said.
Perillo chose the starfish as a research organism “because I wanted to understand the underlying mechanism of tube formation that is conserved in all vertebrates. So I needed an animal that was at the base along the tree of life, [evolving] before chordates.”
Using CRISPR and other techniques to analyze gene function, as well as long time-lapse movies of developing starfish larvae, Perillo and colleagues ascertained how this organism generates tubes that branch out from its gut. Her study identifies a basic toolkit from which chordate tubular organs may have evolved. (Chordates include vertebrates—fish, amphibians, reptiles, birds, and mammals—and a few sub-invertebrates.)
One of the open questions in biology, Perillo said, is exactly how organisms evolve from a single cell to the intricate three-dimensional tubular structures of different organs. In some organisms such as flies, she said, “there is a large round of cell reproduction before all the cells begin to form very complex migration patterns to elongate, change shapes, and become a tube.” In other animals, including mammals, cell reproduction and migration occur together. In the case of starfish, “I found that in order to form a tube, cells can proliferate and migrate at the same time,” as they do in vertebrate development. “So, this means that this organ-making machinery was already established at the base” or root of chordate development, she said.
In addition to providing insight into the basic process that leads to organ formation, sea stars could serve as a model for much biomedical research, Berio suggests. For example, I found that a gene called Six1/2 acts as a master regulator of the branching process in tube formation. In mice, Six1/2 knock-down results in abnormally formed kidneys. But the researchers found that mice lacking this gene also resisted tumor formation, even when injected with cancer cells. The gene, which is overexpressed in cancer cells, could lead to new ways to study disease progression, including cancer.
“I can now use this gene to understand not only how our organs develop, but what happens to the organs when we have disease, especially cancer,” she says. “I hope that in five to ten years maximum, we will be able to use this gene to test how organs develop cancer and how cancer becomes metastatic.”
Starfish embryos have several practical experimental advantages, Berio said. They are often translucent, so the internal growth processes can be directly observed over long periods of growth without harming the organism. They’re also easy to collect and propagate in large numbers throughout the year, “so I always have plenty of material to work with.”