Eric Rulifson, Ph.D.
Developmental Genetics of the Drosophila Neuroendocrine System
We use Drosophila as a model system, with its excellent resources for genetic analysis, to explore the basic mechanisms of pattern formation and gene regulation that underlie the programing of insulin-producing cells and the neuroendocrine system in general. Our work started with the discovery that while Drosophila has no pancreas, it does have cell types with homologous functions to pancreatic islet cells that could be used to address our question of how they are made. We identified a single neural stem cell progenitor (neuroblast) for the brain insulin-producing neurosecretory cells (IPCs) and a second neuroblast for cells that are homologous to the glucagon-secreting islet alpha-cells. As for relevance of our model to its vertebrate counterparts, we found that Drosophila islet-like cell development shares molecular features with both the development of the vertebrate pituitary, neurosecretory hypothalamus and islet, suggesting there is an ancient evolutionary link between endocrine cell development in the head and gut.
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 endocrine progenitor specification, which occurs in neuroectodermal placodes of the embryonic head. We are currently working to address the following questions: How does early segmentation gene regulation, in combination with cell-cell signaling, pattern the field of the neuroectodermal placodes and the endocrine progenitors? What is the gene regulatory architecture that promotes the self-sustained developmental program of this endocrine system? What are the combinatorial codes of transcription factors that specify the various hormone-producing cell types? And, how is the subsequent development of endocrine stem cell lineage genetically controlled to produce the correct number and differentiation of specific cell types?
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?