RESEARCH
1. Physiological functions of GDNF family ligands and their receptors
During development, neurons only become truly functional after establishing connections with appropriate counterpart cells and initiating cell-cell communication. A family of proteins known as neurotrophic factors plays a central role in this intercellular exchange of information. These proteins are secreted from target cells and other sources, and activate specific receptors on neuronal cell membranes, thereby regulating survival, differentiation, or other cell functions. Our team focuses on studying the physiological functions of the GDNF family of neurotrophic proteins and their receptors.
The GDNF family comprises four known members - GDNF, NRTN, ARTN, and PSPN - which bind with a group of receptors known as GPI proteins, which include GFRα1, GFRα2, GFRα3, and GFRα4, to activate RET tyrosine kinase receptors and convey signals to cells.
Genetics research, primarily using mouse as a model, has shown that the GDNF family proteins and their receptors are required for the development of a great many cell types in the central and peripheral nervous systems, including CNS dopaminergic neurons, motor neurons, and enteric neurons. The elucidation of GDNF family functions may therefore be fundamentally useful in developing a deeper understanding of and treatments for pathologies that affect these cells, such as Parkinson disease, amyotrophic lateral sclerosis, and Hirschsprung disease.
2. Mechanisms of enteric nervous system development
The enteric nervous system regulates the movement, secretion, and blood flow of the gut, and is essential for the maintenance of life. This nervous system innervates the lining of the entire length of the intestinal tract with more neurons than are found in the spinal column. Enteric neurons differentiate into multiple subtypes with inter-related physiologic roles, and are capable of controlling basic gut functions even in the absence of input from the brain, for which reason this system is sometimes referred to as "the second brain".
The majority of the cells that make up this most complex of peripheral nervous systems are derived from a relatively limited transient cell population (vagal neural crest cells). When these cells invade the foregut during early development, they differentiate into enteric neuron precursors and begin migrating caudally, away from the mouth and toward the rectum to form the enteric nervous system, one of the longest distances traveled by any group of cells in development. While some of the cells in this population undergo mitotic division, others differentiate into various neuronal cell types. The study of the ontogeny of the enteric nervous system therefore involves a wide range of fundamental developmental processes, including cell migration, proliferation, survival, and circuit formation.
We are engaged in the search for regulatory molecules that work in these developmental routines, as well as the use of time-lapse imaging to gain insights into the behaviors of cells and molecules in the formation of the enteric nervous system. This powerful suite of techniques allow us to track developmental processes over the course of several days in mammalian embryos, for greater time spans than achievable using any other imaging system. We are hopeful that insights gained in the study of the enteric nervous system will lead to a better and more comprehensive understanding of neurodevelopment as a whole.
3. Molecular mechanisms underlying neural crest-related disorders
The developmental population of cells that derives from the neural crest gives rise to a wide variety of peripheral ganglion neurons and glia. Defects in the neural crest can lead to wide range of human diseases, and our group is interested particularly in such pathologies affecting pediatric patients.
Hirschsprung disease
About one in 5000 infants is born with this form of intestinal obstruction, which is caused by a failure of innervation in the distal gut, resulting in chronic intestinal tonicity (contraction) that prevents the movement of digested matter through the bowel. If untreated, this condition can cause inflammation or even perforation of the gut requiring surgical attention. Our laboratory has generated and studies a number of mutant mouse models of this disease to gain a fuller understanding of the etiology and pathology of Hirschsprung disease.
Neuroblastoma
Neuroblastoma is a tumor deriving from the adrenal medulla and sympathetic nervous system, which is the most common form of abdominal malignant tumor in the pediatric population. Prognosis remains poor in cases of metastatic progression, even when treated by combined therapeutic modalities, and thus new approaches to its treatment are desperately needed. We have developed mouse models that we will use to investigate the effects of specific genetic mutations on sympathetic neuronal and adrenal medullar development. Through this approach combining developmental biology and oncology, we will pursue new concepts in the study of cancers of developmental origin.
By developing lines of mutant mouse models of these diseases, we are able to study the function of genetic mutations under otherwise physiologic conditions, and from this gain important insights into disease states and the opening of new pathways toward treatment.