Learning how organs form explains fatal birth defects

October 25, 2013 by Carly Hodes
Learning how organs form explains fatal birth defects
The developing vertebrate gut tube forms loops.

(Medical Xpress)—Symmetry in vertebrates only goes skin deep – many internal organs grow differently left to right. Cornell researchers have discovered a temporary molecular traffic system that starts an embryo's organs growing in the proper direction and without it triggers devastating diseases and defects.

The study, featured on the cover of the Sept. 30 issue of Developmental Cell, inspired an accompanying peer commentary and sheds light on the function of a little-known protein with a big role in organ formation.

The research describes the series of molecular signals that 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," said 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."

Learning how organs form explains fatal birth defects
3-D model of gut tilting morphogenesis.

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 locklike daam2 then interacts with signaling by the keylike 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," said 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 to pack more tightly on the left side of the gut tube. This set the structure for the growing gut to start looping leftward.

Learning how organs form explains fatal birth defects
GI tract of chicken embryo just prior to hatching (day 18).

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," said 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," said 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."

Explore further: Research reveals clues to the formation of hearts, intestines and other key organs

Related Stories

Research reveals clues to the formation of hearts, intestines and other key organs

August 9, 2011
How do the intestines in tiny birds or large mammals form intricate looping patterns? How do hearts and vascular systems form? Why do some large dog breeds succumb to gastric torsion while others don't? Newly released research ...

Researchers offer new insights on cancer cell signaling

July 12, 2013
(Medical Xpress)—A pair of studies by a team of University of Notre Dame researchers led by Crislyn D'Souza-Schorey, professor of biological sciences, sheds light on a biological process that is activated across a vast ...

Scientists pinpoint proteins vital to long-term memory

September 12, 2013
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found a group of proteins essential to the formation of long-term memories.

How does pregnancy reduce breast cancer risk?

April 29, 2013
Being pregnant while young is known to protect a women against breast cancer. But why? Research in BioMed Central's open access journal Breast Cancer Research finds that Wnt/Notch signalling ratio is decreased in the breast ...

Wnt signaling pathway plays key role in adult nerve cell generation: study

September 10, 2012
Researchers from the University of Utah have gained new insight into the regulation of adult nerve cell generation in the hypothalamus, the part of the brain that regulates many aspects of behavior, mood, and metabolism. ...

Experimental 'stapled peptide' drug blocks key cancer molecule

August 24, 2012
(Medical Xpress)—US scientists have developed an artificial molecule called a 'stapled peptide' that can shut down the cancer-fuelling effects of a molecule called Wnt. 

Recommended for you

Team finds link between backup immune defense, mutation seen in Crohn's disease

July 27, 2017
Genes that regulate a cellular recycling system called autophagy are commonly mutated in Crohn's disease patients, though the link between biological housekeeping and inflammatory bowel disease remained a mystery. Now, researchers ...

Study finds harmful protein on acid triggers a life-threatening disease

July 27, 2017
Using an array of modern biochemical and structural biology techniques, researchers from Boston University School of Medicine (BUSM) have begun to unravel the mystery of how acidity influences a small protein called serum ...

CRISPR sheds light on rare pediatric bone marrow failure syndrome

July 27, 2017
Using the gene editing technology CRISPR, scientists have shed light on a rare, sometimes fatal syndrome that causes children to gradually lose the ability to manufacture vital blood cells.

Post-stroke patients reach terra firma with new exosuit technology

July 26, 2017
Upright walking on two legs is a defining trait in humans, enabling them to move very efficiently throughout their environment. This can all change in the blink of an eye when a stroke occurs. In about 80% of patients post-stroke, ...

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.