Pediatrics / Pediatric Surgery
Summary of Research
Enteric Nervous System Development
My laboratory is interested in the development of the enteric nervous system (ENS), a complex neuronal network whose principal function is to maintain normal intestinal motility. Congenital abnormalities of the ENS are responsible for severe gastrointestinal disorders in childhood, including Hirschsprung’s disease, intestinal pseudo-obstruction, and other causes of dysmotility. The ENS is made up of neurons and glia that arise from the neural crest and migrate along the length of the intestine. Proteins in the intestinal microenvironment interact with factors expressed on the crest-derived cells to direct their migration, proliferation, survival, and differentiation. Hirschsprung’s disease results from the absence of ganglion cells along a variable length of distal intestine, leaving affected children with a severe functional obstruction. While several genetic mutations are associated with Hirschsprung’s disease, the mechanism of action of these genes, as well as the identity of their upstream regulators and downstream targets, remain poorly understood. Additionally, the genetic basis of other neuro-intestinal diseases is entirely unknown.
In our laboratory we use the avian embryo as a model system to study ENS development. Using a variety of techniques, including retroviral-mediated gene misexpression, chick-quail chimeras, coelomic transplantation, and organ culture techniques, we have thoroughly characterized normal development of the colorectal ENS. We have also identified essential roles for bone morphogenetic proteins and endothelin-3 during ENS formation in the hindgut, the portion of intestine most commonly affected in human congenital disorders of the ENS. Ongoing projects include:
- Elucidating the role of sonic hedgehog, bone morphogenetic proteins, endothelin-3, and glial-derived neurotrophic factor (GDNF) signaling during ENS development
- Understanding how the various molecular pathways involved in colonic enteric nervous system development interact with each other.
- Defining the role of a novel gene in development of the ENS and the autonomic nervous system
- Examining the ganglion cells and interstitial cells of Cajal in colorectal biopsies from patients with abnormalities of intestinal motility
Understanding the molecular factors required for normal ENS development will give us new insights into the pathophysiology of neuro-intestinal disorders and allow us to develop novel diagnostic and therapeutic approaches to the management of children with these serious conditions.
Contact information
Phone: 617-726-0270
Fax: 617-726-2167
E-mail: agoldstein@partners.org
