Regulation of generation and functions of intermediate progenitors

Intermediate progenitors are stem cell progeny that undergo limited proliferation to increase the generation of differentiated cells per asymmetric stem cell division. Subsets of stem cells appear to have the capability to further expand the generation of intermediate progenitors via transit-amplifying cell types while other subsets do not. It is unclear whether the competency to amplify the generation of intermediate progenitors is encoded in the lineage-specific gene regulatory program or is a general stem cell functionality that can undergo controlled activation. In addition, stem cell functionalities must become decommissioned in intermediate progenitors to ensure that they exclusively generate differentiated cell types. The mechanisms that decommission stem cell-specific functions are not understood. This proposal uses fruit fly neural stem cell (neuroblast; NB) lineages as a model to define the driver and the barrier to amplify ganglion mother cells (functional analogs of intermediate progenitors in vertebrates) via intermediate neural progenitors (INPs). We defined 4332 neurogenic enhancers that likely play important roles in specifying cell type-specific gene expression in the developing brain. By using this collection of neurogenic enhancers, we identified 43 candidate transcription factors that regulate the competency to generate INPs. In parallel, we also identified 35 transcription factors that likely function to promote decommissioning of type II NB functionality genes genes in INPs. By initially focusing on these genes, we will begin to define the mechanisms that (1) control NB competency to generate INPs and (2) decommission NB functionality genes in INPs. Our proposed experiments will provide insight into how dynamic control of neurogenic enhancers promotes (1) the competency to expand intermediate progenitors via transit-amplifying cell types and (2) decommissioning of stem cell-specific functions in intermediate progenitors.