Wnt pathways

One of our research interests is to delineate the Wnt signaling pathways that control early development. Three Wnt signaling pathways conserved from fly to human are known: Wnt/b-catenin (canonical), Wnt/cGMP/Ca²⁺ (non-canonical), and planar cell polarity (Wnt PCP) pathway. Disruption of Wnt pathways blocks development and induces early death. Abnormal activation of Wnt/b-catenin pathway, in particular, induces cancer. We established that Wnt signaling pathways are G-protein-coupled signaling pathways. Recently, my laboratory has identified IP₅, an unexpected signal molecule downstream of the effectors of G-proteins, as a mediator of Wnt3a signaling, operating at the level above GSK3b in Wnt//b-catenin pathway. One of our research focuses is to understand the mechanism by which IP₅ is generated in response to Wnt3a stimulation. We are studying the basis for the IP₅ inhibition of GSK3b activity.

With respect to Wnt non-canonical pathway, an example of this pathway is one that mediated by Frizzled-2, Gat and Gao, regulating cyclic GMP accumulation and Ca²⁺ mobilization. The mobilization of intracellular Ca²⁺ is essential for Wnt5a activation of NF-AT-sensitive gene transcription. Currently we are studying the role of Dishevelled, a well-known and important scaffolding protein in Wnt/b-catenin, in the transduction of Wnt non-canonical signaling.

The role of Wnt/Frizzled pathways in differentiation and self-renewal of Human embryonic stem cells

Human embryonic stem cells (hESC) provide both a great model for analysis of cell signaling and development as well as a source of therapeutically important cells. Human ESC are totipotent and their therapeutic potential is highest if they can be provoked to defined stem cell populations that are homogenous and predictable in their growth and end-point differentiation (e.g., cardiac muscles cells, pancreatic beta cells, neural cell types). The inherent heterogeneity of hESC must be overcome if well-defined end-point populations are to be created, interrogated for their individual cell-type specific gene expression, and employed in therapeutics. Wnt ligands act on Frizzleds to guide cell development. We are using a novel method by which stimulation of each Frizzled can be achieved without a Wnt (which can activate more than one Frizzled type). We plan to characterize self-renewal of hESCs and the way hESCs can be programmed to differentiate.