Eric Rulifson, PhD

Core

Our main research goal is to understand the cell differentiation pathway of insulin-producing cells, such as pancreatic islet beta-cells. Loss of insulin-producing beta-cells underlies the endpoint of diabetes type I and II. A key to treating these diseases lies in understanding the developmental pathway of beta-cells and applying this to the programming of stem cells for beta-cell replacement. With a desire to contribute to the treatment and cure for diabetes, we have turned to the fruit fly and genetics to study the developmental origins and cell biology of the pancreatic islet cells in a model system.

Drosophila has no pancreas, but the fly does have cell types with homologous functions to pancreatic islet cells. We have now identified a single neural stem cell progenitor (neuroblast) for the brain insulin-producing neurosecretory cells (IPCs), which are analogous to islet beta-cells. Likewise, we identified a second neuroblast for cells of the corpora cardiaca that are homologous to the glucagon-secreting islet alpha-cells. Remarkably, both progenitors originate as neighboring cells within an anterior head neuroectoderm domain that shares striking molecular orthology to the vertebrate hypophyseal placode, the source of endocrine anterior pituitary and neurosecretory hypothalamic cells. This ontogenic-molecular concordance suggests that the brain endocrine axis arose originally in the common ancestor of humans and flies, where it orchestrated islet endocrine functions with insulin and glucagon-like hormones. The fact that the insulin and glucagon-secreting cells are specified from a common anlage in both flies and vertebrates suggests that there are evolutionarily conserved cell specification mechanisms for brain endocrine cells and pancreatic islet cells.

The development of the Drosophila neuroblast lineage is a well established and powerful paradigm to understand the genetic control of cell fate specification and organogenesis. Guided by this basic paradigm, we are beginning to dissect the genetic control of the two lineages that generate the fly islet-like cells. We are currently working to address the following questions: How do the "placode genes" control development of IPC and CC cell lineages? How does the early segmentation gene hierarchy establish the expression of placode genes in the anterior head? How is the further compartmentalization and patterning of this region achieved? Is there a combinatorial code of gene activity that is sufficient to specify these cells? How is the stem cell lineage genetically controlled to produce the correct number and fates of cells? Most importantly, which of these mechanisms play a role in beta-cell programming in people, and how can this information be applied to the programming of beta-cells from embryonic and other adult stem cells?