Intercellular communication is critical for development and function of all multicellular organisms. Dysregulation of intercellular signaling during development leads to embryonic malformations (i.e. birth defects); during later life it can lead to improper cell proliferation and differentiation (i.e. cancer). One major role that intercellular signaling plays throughout life is in regulating stem cell maintenance and differentiation. This ensures that stem cells give rise to the correct types of tissues in the right places at the right times during development. It also ensures that some stem cells are set aside for later needs during the life of the organism (i.e. adult stem cells).
Dysregulated intercellular signaling may also contribute to adult-onset diseases characterized by dearth of a crucial cell type. Prominent examples of this (among many) include insufficient dopamine-producing neurons in Parkinson’s disease, or insufficient insulin-producing pancreatic islet cells in Type I Diabetes. Conceptually, such diseases can arise by one or a combination of several mechanisms: 1. decreased generation of initial cell numbers during development, 2. decreased survival of cells during adulthood, 3. decreased regeneration of new cells (i.e. from adult stem cells) to restore those lost to attrition. Cellular responses to extracellular signaling cues are important for all three of these mechanisms. Discovering how genes contribute to cellular signaling responses is therefore a critical component of understanding how such diseases arise, as well as how to most effectively treat them.
The major focus in my laboratory is on clarifying functions of cytoplasmic molecules called scaffold proteins. Though their cell biology is not very well understood, scaffold proteins within signal-receiving cells help to mobilize other components into a signal transduction machinery. The type of signal transduction machinery assembled depends on the cell’s developmental history, its internal molecular environment, and its signaling state. Scaffold proteins thereby help to determine which molecular events occur inside a signal-receiving cell upon activation of a membrane receptor complex by an extracellular ligand. This in turn determines the signal-receiving cell’s biological response to the extracellular signal. This has direct relevance to therapies which hope to use extracellular signals to manipulate stem cell proliferation, differentiation, and the survival and function of differentiated progeny with the ultimate objective of replacing tissues or cells lost to disease.
We are particularly interested in studying this with relevance to neuropsychiatric disease processes in the brain, and we use genetically engineered mice and