A novel zebrafish model enables genetic studies of Hirschsprung disease

January 12, 2017, The Francis Crick Institute

Researchers led by the Francis Crick Institute have developed a zebrafish model of a human disease - Hirschsprung disease - that enables them to study the disease's causes and consequences in living animals and will help develop new treatments.

Tiffany Heanue, working in Vassilis Pachnis's group at the Crick, says: "Hirschsprung is a complex disorder and many factors contribute to the development of this condition. This has many advantages over existing mouse models, and will enable us to identify whose defective function result in the disease."

Hirschsprung disease is characterised by a lack of nerve cells in the gut, which disrupts the usual relaxation and contraction of needed to move the gut's contents along its length. It is usually diagnosed soon after birth and can be caused by defects in many genes. The disease is fatal if untreated.

The network of neurons in the gut are referred to as the enteric nervous system (ENS). In patients with Hirschsprung disease, ENS cells are missing from the far (distal) end of the colon, resulting in permanent smooth muscle contraction of this part. This stops the normal flow of gut contents.

Almost all patients with Hirschsprung disease have mutations in a gene called RET as well as mutations in other genes, many of which remain unknown.

The researchers studied zebrafish with a mutation in the ret gene and found that nerve cells were absent in the distal gut. Interestingly, animals were either severely or mildly affected, mimicing the variation in clinical severity seen in Hirschsprung patients. An advantage of the scientists' approach was that they were able to directly observe the and follow gut muscle contractions in the transparent zebrafish larvae using live imaging.

This robust animal model will enable studies of the role of other genes that have been suggested to affect the severity of Hirschsprung disease. Indeed, this approach was used to confirm the contribution of one such gene (MAPK10) to ENS function and Hirschsprung disease.

Dr Heanue says: "At the moment we can't carry out genetic testing or counseling for Hirschsprung disease because different gene mutations contribute to the condition and the interactions between them are not yet understood. We expect that future use of our zebrafish model will help identify which genes are important. As disease associated genes are identified, and their roles studied, the possibility for genetic counseling increases."

Dr Pachnis says: "The ability to directly examine actual gut movement in living zebrafish larvae can, in the future, be combined with methods to examine nerve circuits and activity. This could build our understanding of the organisation of nerve circuits that regulate actual functional outputs in real time."

Explore further: New genetic clues emerge on origin of Hirschsprung's disease

More information: Tiffany A. Heanue et al. A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity, PLOS Genetics (2016). DOI: 10.1371/journal.pgen.1006439

Related Stories

New genetic clues emerge on origin of Hirschsprung's disease

April 3, 2015
Genetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung's disease. The findings add to an increasingly clear picture ...

Noncoding mutations disrupt cooperative function of 'gene families' in rare genetic disorder

September 30, 2016
Scientists at Johns Hopkins say they are one step closer to understanding the genetic mechanism of a rare, complex, multiple-gene disorder called Hirschsprung's disease. The results of their latest study suggest that many ...

Research offers novel insight into Hirschsprung's disease

January 15, 2015
Defects in the protein Sox10, a transcription factor that regulates gene expression, may play a role in the development of post-operative GI dysfunction in Hirschsprung's disease patients, according to new research published ...

Tissue-engineered colon from human cells develop different types of neurons

October 1, 2015
A study by scientists at Children's Hospital Los Angeles has shown that tissue-engineered colon derived from human cells is able to develop the many specialized nerves required for function, mimicking the neuronal population ...

Discovery of gene effects on brain brings scientists closer to understanding rare developmental disorder

January 11, 2017
Scientists are closer to finding additional genetic causes for the rare developmental disorder Cornelia de Lange Syndrome after discovering the steps in brain development that may be affected in some patients.

Recommended for you

Targeting the engine room of the cancer cell

June 18, 2018
Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug ...

Scientists learn more about how gene linked to autism affects brain

June 18, 2018
New preclinical research shows a gene already linked to a subset of people with autism spectrum disorder is critical to healthy neuronal connections in the developing brain, and its loss can harm those connections to help ...

161 genetic factors for myopia identified

June 15, 2018
The international Consortium for Refractive Error and Myopia (CREAM) recently published the largest-ever genetic study of myopia in Nature Genetics. Researchers from the Gutenberg Health Study at the Medical Center of Johannes ...

Genetic disorder identified in children

June 15, 2018
A genetic defect affecting normal development in children has been identified by a study involving University of Queensland researcher and alumnus Professor David Coman.

Scientists discover biomarker for flu susceptibility

June 13, 2018
Researchers at the Stanford University School of Medicine have found a way to predict whether someone exposed to the flu virus is likely to become ill.

Brain secrets that flow in our blood

June 13, 2018
Our blood can be used to uncover genetic secrets inside the brain, according to University of Queensland research.

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.