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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 disease is a complex disorder and many
factors contribute to the development of this condition. This
zebrafish model has many advantages over existing mouse models, and
will enable us to identify genes 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
smooth muscle 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 nerve cells 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."
The paper, A Novel Zebrafish ret Heterozygous Model of
Hirschsprung Disease Identifies a Functional Role for mapk10 as a
Modifier of Enteric Nervous System Phenotype Severity, is
published in PLOS Genetics.