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A paradigm shift in Hirschsprung disease: zebrafish modelling to identify non-neuronal factors

Project summary

Hirschsprung disease (HSCR) is a rare congenital gastrointestinal malformation characterized by lack of the enteric nervous system (ENS), aganglionosis, in the distal gut. The aganglionic segment is often limited to the sigmoid colon and rectum. Several scenarios have been proposed to explain this aganglionosis. The commonly described and most studied one is that the progenitors of the ENS, the enteric neural crest cells (ENCCs), do not reach the distal part of the colon, due to migratory or proliferation problems.

Current treatment for HSCR is surgical removal of the affected aganglionic region. However, surgical intervention does not prevent further complications for the patient, including enterocolitis, faecal incontinence or chronic constipation. A search for alternative therapy is therefore, warranted.

Since the known HSCR genes only explain approximately 30% of all cases, and almost all research has so far focused on genes expressed in neurons, it is tempting to suggest that genes expressed in non-neuronal cells, composing the micro-environment of the ENS play an important role. These cells communicate with ENCCs, thereby affecting their function, and thus, might play a role in disease development. Identification of affected signaling pathways within these cells, could have a strong impact on the field, as they can potentially be manipulated to prevent or revert aganglionosis in HSCR patients, and to increase grafting ability of transplanted ENCCs. They are also perfect candidates to explain the missing heritability of HSCR.


This projects will give us insight in the development and functioning of the ENS at a molecular level. Besides, we will increase our understanding of the genetic component of HSCR. By generating genetic and non-genetic HSCR models, we can start searching for small molecules that could stimulate the colonization of the gut by ENS progenitors. This could ultimately lead to the validation of new drugs that could prevent aganglionosis and/or improve HSCR patients’ intestinal innervation.

More detailed information

Principal Investigator:

Role Erasmus MC:



Project website:

Not available

Funding Agency:

Stichting Vrienden van Sophia