The Rosenblatt Lab studies both cell death and cell division and the roles that the actin and microtubule cytoskeletons play in both processes. Our lab is investigating if extrusion (a contraction that squeezes dying cells out of tissue) could drive cell death in order to control cell numbers.
- BA, Molecular Biology/Transcription, University of California at Berkeley. Project: The role of puffing of polytene chromosomes in transcription.
- PhD, Biophysics and Biochemistry, University of California at San Francisco. Project: Regulation of actin dynamics
The goal of my research program is to investigate the signaling and mechanisms that control cell extrusion, and what governs the direction a cell extrudes from an epithelium. I previously discovered a process that epithelia use to remove dying cells while maintaining a functional barrier, termed ‘extrusion’. We have recently identified that cells destined to extrude produce a lipid, Sphingosine 1-Phosphate, which binds a G-protein coupled receptor (S1P2) in neighboring epithelial cells to extrude them. Inducing cell death triggers cell extrusion to ensure that no gaps form in the epithelial barrier. However, more importantly, we have recently found that normally epithelial cells die by extrusion—crowding induces lives cells to die, which die from detachment of the underlying matrix and its survival signaling. Extrusion is critical for preventing tumor formation, as disrupting the signaling pathway driving extrusion causes cells to lose contact inhibition and form epithelial masses. Although cells normally die following extrusion, aggressive tumor cells that typically upregulate survival signaling could use extrusion to escape their primary sites within epithelia. Their eventual fate depends on the direction that they extrude, as apical extrusion could still suppress tumor formation by eliminating cells through the lumen, whereas basal extrusion beneath the epithelium could enable cells to invade. Importantly, oncogenic mutations in APC, KRas, or AKT drive cells to extrude basally, suggesting that basal extrusion could be key for aggressive tumors harboring these mutations to become invasive and metastatic. To test if basal extrusion can initiate invasion in a model system where we can also manipulate gene function using transgenics, morpholinos, mutants, or inhibitors, we have developed an in vivo model for simple epithelia using zebrafish epidermis. The optical clarity of zebrafish epidermis allows visualization of single cell movements, divisions, and cell extrusion/death critical to testing the fate of cells that have invaded from the epidermis without causing a wound healing response intrinsic to intravital filming non-transparent organisms. Further, we have made lines to drive gene expression specifically in the basal or surface epidermal layer, or in specialized epidermal cells. Additionally, my lab has been investigating the role of failed extrusion in promoting epithelial and endothelial barrier function diseases such asthma and cerebral cavernous malformations.