Park Lab

In developmental biology, we study how complexity is achieved from simplicity. A single cell embryo manages to give rise to all of the different types of cells found in the whole organism through a series of cell fate decisions.

Our lab is interested in how stem/progenitor cells make their decisions about whether to stay in the stem/progenitor state or to differentiate into specific types of differentiated cells. In most cases, these cell fate decisions are controlled by several major signaling pathways, such as the Wnt and Notch pathways. We investigate how these pathways regulate cell fate decisions during development. Currently, we are focusing on cell fate regulation during the organogenesis of the kidney and bladder.

Nephron progenitors express Six2, a transcription factor that is required for progenitor self-renewal. Differentiation of nephron progenitors is induced by Wnt/b-catenin and Notch signals. We have shown that Six2 represses differentiation of nephron progenitors by preventing Wnt/b-catenin signaling from activating key differentiation genes, such as Fgf8 and Wnt4. Once expression of Six2 is downregulated, nephron progenitors undergo differentiation by responding to Wnt/b-catenin and Notch signals.

During development, a handful of signaling pathways are utilized repeatedly in the generation of various types of cells. Wnt, Notch and Hedgehog pathways are some of the major signaling pathways. Transcriptional outcomes of activation of these signaling pathways depend on the cellular context. For example, while activation of Wnt signaling in nephron progenitor cells increases expression of Wnt4 and Fgf8, Wnt signaling in intestinal stem cells activates a different set of genes, such as Lgr5 and Sox9. We are interested in how activation of one signaling pathway regulates expression of different sets of genes in different cell types. Our hypothesis is that transcriptional regulators acting downstream of a signaling pathway interact with endogenous transcription factors that are unique to each cell type and that these interactions determine which target genes will be regulated in each cell type.

In this scheme, the cell on the left expresses transcription factors A, B, C, and D and the cell on the right expresses transcription factors X, Y, and Z. Interaction of the Tcf/b-catenin complex with the respective transcription factors likely determine which target genes are activated by Wnt/b-catenin signaling.