A temporary set of signals get an embryo’s internal organs growing in the right direction.
Those signals are critical for avoid devastating birth defects, according to a new study in the journal Developmental Cell that describes how the signals instruct the intestines to loop counterclockwise, ensuring that they can fit untangled into the abdomen.
Emerging from research on the mid-gut in chicken embryos, the findings suggest how other vertebrates may form other asymmetric organs, including the heart, and reveal previously unknown behavior from a gene important in cancer research.
“What we’ve learned about how organs take shape reveals what may contribute to fatal birth defects and other diseases that arise when organs form at random, opening new paths for diagnosis and prevention,” says principal investigator Natasza Kurpios, assistant professor and a developmental biologist at Cornell’s College of Veterinary Medicine. “It may also have broad implications for cancer research.”
Temporary proteins take sides
Embryos with randomly positioned organs do not survive. Called heterotaxia, this condition’s roots trace to mutations in the gene pitx2, which is only found in the left side of the body.
After determining how pitx2 builds organs, Kurpios’ lab found that during a critical construction day early in intestinal growth, before the looping begins, pitx2 directs production of a protein called daam2 only on the left side of a harnesslike tissue that holds the developing intestine in place.
The lock-like daam2 protein then interacts with signaling by the key-like “wnt” protein, arriving in a flood from the attached intestine. Together these players set up a temporary traffic-control system for intestinal cells.
With daam2 present only on the left, the effects of wnt are felt only on this side. These effects are dramatic: In all species from humans to fruit flies, wnt is crucial to cell proliferation, migration and multiple other cell behaviors, including tissue polarity.
“Wnt is critical for telling individual cells in an organ which way is up,” says Kurpios.
Ian Welsh, a graduate student working in Kuprios’ lab and first author of the paper, found evidence that daam2 was activated around the same time, suggesting a new role for wnt in organ asymmetry. Once activated by wnt, daam2 directed and reorganized the growing number of intestinal cells to pack more tightly on the left side of the gut tube. This set the structure for the growing gut to start looping leftward.
These events occurred only for a day and entirely on the left side of the intestine. On the right side, Kurpios’ lab found inhibitors that disabled wnt.
The brief partnership between wnt and pitx2 occurred in gestation day four in chickens and day 10 in mice. They cooperated at exactly the right place at exactly the right time to start the intestines growing in the correct direction and then never interacted again.
“This study will help clarify the molecular mechanisms of mid-gut malrotations [that] lead to devastating gut disorders,” says Olga Klezovitch and Valeri Vasioukhin of the Fred Hutchinson Cancer Research Center in the study’s accompanying commentary.
“Despite its broad importance, the ways wnt controls cell behavior are still being worked out,” says Kurpios. “The discovery of wnt’s partnership with pitx2 and daam2 may, therefore, also inform ongoing studies exploring wnt’s role in a variety of cancers.”
The National Institutes of Health and March of Dimes supported the study.
Source: Cornell University