Research Summary

Our primary goal is to understanding the molecular regulation of neural stem and progenitor cells in the telencephalon, the embryonic structure that gives rise to the cerebral cortex, hippocampus, amygdala, and basal ganglia. By understanding how neural stem cells are regulating, both in terms of proliferation and the generation of neurons and glia, we will gain insight relevant both to the etiology and treatment of brain cancer, and also to the development of cell replacement strategies to treat the damaged or degenerating nervous system. In addition, we have recently become interested in understanding the signaling events that regulate neuronal plasticity, and in the study of embryonic stem cell derived human neural progenitors.

Ongoing projects in the lab include:

Notch signaling in embryonic neural stem/progenitor cells. We have found that the Notch signaling pathway is differentially utilized in neural stem cells (NSCs) and intermediate neural progenitors (INPs). In NSCs, Notch signals through the canonical effector CBF1 (also called RBP-J and CSL), while in neuroblasts this signaling cascade is attenuated and/or redirected to non-canonical targets. We use our transgenic Notch reporter (TNR) mouse line, which expresses EGFP in cells with Notch/CBF1 activation, to separate these populations prospectively for study. Ongoing efforts are designed to characterize the lineage relationship between NSCs and INPs, to identify the molecular mechanisms through which Notch signaling is differentially regulated in NSCs and INPs, and how these cell types differ on a molecular level at large. Of particular interest, we are examining the role of the transcriptional regulator Zbtb7a/LRF/Pokemon, which has been shown to antagonize Notch signaling during cell fate specification in the immune system.

Notch3 and tumor formation. In collaboration with Dr. Charles Eberhart (Pathology Dept., JHU Med), we have found that an activated form of Notch3 can promote tumor formation in mice. Specifically, we have found that Notch3 activation leads to the formation of choroid plexus tumors (CPTs) and also to invasive ocular tumors. We are characterizing the origin and progression of the ocular tumors, which appear to be derived from both neural and non-neural cell types, and are akin to astrocytomas and ocular melanomas, respectively. In addition, was have found that unlike Notch3, activated Notch1 does not cause CPTs or ocular tumors. We are interested in identifying the molecular differences between Notch3 and Notch1 that make the former, but not the latter, tumorigenic in our system, and are performing domain exchange experiments to address this issue.