My interests in the lab revolve around identifying mechanisms of normalmammalian development, in order to then use this knowledge to elucidatepathological processes.During development, cells divide to increase their numbers and specializeto form complex functional organs, such as the liver.The mammalian livergrows rapidly to become the largest gland in the body.How is growth andcell division controlled during this process? To explore this question, wefocused on the Wnt signaling pathway, a short-range cell-cellcommunication signal, which is necessary for liver growth. Wnt ligands arereleased by endothelial cells of the central veins in the liver. Nearby peri-central hepatocytes receive and respond to Wnt signals by activatingtranscription factors such as the T-BOX3 (TBX3) transcriptional repressor.We found that TBX3 represses expression of two important cellcycleinhibitors, E2f7 and E2f8. Through this double-negative mechanism Wnt-Tbx3 signaling promotes division of hepatocytes during the postnatalgrowth phase. In fact, in the absence of TBX3, expression of E2f7/8increases and hepatocytes arrest in mitosis to become polyploid, which canlead to fibrosis in the tissue.I am also interested in mechanisms of embryonic liver development andhow the Wnt-Tbx3 expression pattern, which persists into adulthood, isestablished. Finally, using multi-color geneticlineage tracing and confocalmicroscopy, I have been visualizing and measuring the rate and location ofhepatocyte cell division during development. With these methods, I aim toidentify patterns of tissue growth in the liver.
Antibody staining shows hepatocyteswith nuclear Tbx3 surrounding the central vein (CV)
We deleted Tbx3 from hepatocytes inneonates and collected livers at 3 weeks after birth. We can see overlypolyploid nuclei appearing in the Tbx3KO livers. This is due to a mitoticarrest and failure in complete cell division in the absence of Tbx3
Using Tbx3-CreERT2;confetti mice, we can label and lineage trace. Tbx3-expressing cells and their growth around the vascular tree (marked in white)