Hirschsprung Disease and Development

Hirschsprung disease and enteric nervous system development:  This page is devoted to a few simple questions.  (Please refer to the Glossary  for an explanation of medical terminology.)

What causes Hirschsprung disease? 

Can we make Hirschsprung disease less likely to occur? 

Are there any new treatment strategies?

Since Hirscshprung disease is a problem of early human development, the anwers to these questions lie in understanding how development occurs normally.  Human development is directed by information in our DNA and can be influenced by non-genetic factors.

Why do we study development?  We want to find new ways to prevent human birth defects. Birth defects are anatomic problems that occur when development does not occur normally.  Development is the process of forming a complex organism (like a baby) from a fertilized egg.  As a pediatric gastroenterologist I care for many children whose medical problems stem from abnormal prenatal development.  Our work to understand the mechanisms of normal enteric nervous system developement have led us to conclude that some cases of Hirschsprung disease may be preventable, but we will need to do more work in model systems and in human populations to prove our hypothesis.

What do we know about how the enteric nervous system forms?  While many questions remain unanswered, we know a lot about the cells that form the enteric nervous system and the molecules that guide their development.  Some of what is known is summarized below.

Cellular Mechanisms of Enteric Nervous System (ENS) Development:

The ENS is derived from a small population of neural crest cells that originate in the vagal (mouse somites 1-5), sacral, and upper thoracic (mouse somites 6 and 7) portions of the neural tube.  Vagal crest-derived precursor cells migrate all the way down the bowel in a proximal to distal direction and are the major source of enteric neurons and glia.  Sacral crest derived cells provide a small percentage of the ENS in the distal bowel.  Thoracic neural crest derived cells populate only the esophagus and stomach.  For this reason, vagal crest derived ENS precursor cells are the most well studied ENS progenitors.

As ENS precursors migrate through the gut they actively proliferate to make enough cells to populate the bowel.  These cells then exit the cell cycle and differentiate into neurons or glia that form an extensive interconnected functional network.

We are interested in identifying and characterizing the molecules that control ENS development.  For this reason, we study a wide range of trophic factors, adhesion molecules, transcription factors, signaling molecules and morphogens.  Some of our recent publications can be found here

Genetics of Human Hirschsprung Disease and Molecular Mechanisms of ENS Development:

Because of the complex cellular pathway required to form the enteric nervous system, many molecules are required for normal ENS development.  These pathways have been reviewed in detail (Review 1Review 2Review 3Review 4, Review 5 (our review)), and some important features will be summarized here.  Molecules discussed are organized by function.  Defects in these molecules predispose to Hirschsprung disease:

(Note:  We have published papers about many of these proteins including RET, GFRalpha1, GDNF, EDN3, ECE1 and BMP4).  Our work is most easily found by typing "Heuckeroth" and into the PubMed search box.)

Cell surface molecules:

RET: Transmembrane tyrosine kinase.  Activated by GDNF, neurturin, artemin and persephin via four different GFRalpha receptors.  Supports ENS precursor cell survival, proliferation, migration, neuronal differentiation and neurite growth.  Most people with Hirschsprung disease have RET mutations. 50% of children with Hirschsprung disease who have affected family members and 25% of people with "sporadic" Hirschsprung disease have an inactivating mutation in one allele of RET.  Most other people with Hirschsprung disease have an enhancer polymorphism that reduces RET expression.  In rare cases where both alleles of RET are inactivated, babies are born with no neurons in the entire bowel. In the more commoon case where a single RET allele is inactivated, 70% of males and 50% of females have Hirschsprung disease.  In uncommon cases, RET activating mutations may also cause Hirschsprung disease and predispose to the inherited cancer syndrome called Multiple Endocrine Neoplasia 2A (MEN2A).  (RET link)

GFRalpha1 (GFRA1): Co-receptor for RET.  A glycosylphosphatidylinositol linked protein that binds GDNF and activates RET in response to this ligand.  GFRalpha1 mutations may occur in people with Hirschsprung disease, but this is rare. (GFRalpha1 link).

Endothelin receptor B (EDNRB): Transmembrane G-protein coupled receptor.  Activated in ENS precursors in response to endothelin-3 (EDN3).  Reduces the likelihood that precursors will differentiate and facilitates migration into the distal colon.  Mutations in EDNRB are found in about 5% of people with Hirschsprung disease.  EDNRB mutations typically cause short segment Hirschsprung disease (95% of the time) and features or Waardenburg syndrome type 4 (WS4) including pigmentation abnormalities (white forelock, premature graying, pigment loss in the iris, congenital sensorineural hearing loss).  (EDNRB link).

Transcription factors (Proteins that bind DNA to control gene expression. Each has many targets):

SOX10: Activates RET and MITF, key genes for enteric nervous system and melanocyte (skin pigment cells) respectively.  Mutations cause Waardenburg syndrome type 4 (WS4).  (SOX10 link).

PHOX2B: Activates RET expression.  Mutations cause Hirschsprung disease and congenital central hypoventillation syndrome (CCHS). (PHOX2B link).

ZFHX1B: Downregulates (reduces expression) of E-cadherin and bone morphogenic protein 4 (BMP4).  This activity is required for efficient migration of neural crest cells from the neural tube.  Mutations in ZFHX1B cause Mowat-Wilson syndrome. This syndrome includes mental retardation, delayes motor development, epilepsy, Hirschsprung disease and distinctive facial features. (ZFHX1B link).

PAX3: Increases RET and MITF expression synergistically with SOX10.  Mutations cause Waardenburg syndrome with or without Hirschsprung disease.  (PAX3 link).


Endothelin converting enzyme 1 (ECE1): An enzyme that produces EDN3 from a larger precursor protein ("big endothelin").  Defects cause Hirschsprung disease, heart defects and changes in facial structures. This is a rarely identified mutation in children with Hirschsprung disease. (ECE1 link).

Extracellular proteins:

Glial cell line-derived neurotrophic factor (GDNF): A secreted protein that binds GFRA1 and activates RET.   Although there are four RET ligands, only GDNF is required for ENS precursor survival, proliferation and migration during early development.  GDNF mutations have been rarely identified in people with Hirschsprung disease (GDNF link).

Endothelin-3 (EDN3): A secreted 21 amino acid peptide that binds to and activates EDNRB. Inactivating mutations cause Waardenburg shaw syndrome type 4 (WS4). This is a rarely identified mutation in children with Hirschsprung disease.  (EDN3 link).

Chromosomal defects:

Trisomy 21 (Down syndrome): An extra copy of chromosome 21 causes this disorder.  There are many features of Down syndrome, including an increased risk for Hirschsprung disease.  Approximately 1:100 people with Down syndrome have Hirschsprung disease. (Down syndrome link).

There are also many (i.e., >30) genetic syndromes associated with Hirschsprung disease.  These syndromes are summarized in an article by Amiel et. al.  

Stem Cells and Novel Strategies for Treating Intestinal Motility Disorders:

The recent discovery of stem cells for the enteric nervous system within the newborn and adult bowel has spurred an exciting new phase of research with the potential to revolutionize management for Hirschsprung disease and other human intestinal motility disorders.  These studies are just beginning so treatment is not yet available.  Manuscripts that provide additional information about this field of research can be found here (Review 1Review 2Review 3, Review 4).