Roeland Nusse

Research/Lab website:   Nusse Lab Home Page

During the developmental of an animal, cells become progressively and stepwise committed to specialized fates. Many of the decisions that cells make during embryogenesis are regulated by a relatively small number of signaling factors, including the Wnt, BMP and Hedgehog proteins. During the regeneration and renewal of adult tissue, the same signals control how stem cells divide. Unrestrained Wnt signaling, after mutations in Wnt signaling components, is implicated in cancer, including human colon cancer.
Our laboratory has a long-standing interest in the activity of Wnt proteins during embryogenesis and other processes. One of our major recent contributions to the field has been to develop methods to purify Wnt proteins in an active form. With the purified proteins, we could establish that Wnt proteins are modified by fatty acids. We have also used the purified Wnt proteins to manipulate the behavior of stem cells in culture, in particular neural stem cells. We have evidence that those stem cells respond to Wnt signals in vivo, in structures called niches.
We are also interested in Wnt signaling during the repair of damaged tissue. This follows the evidence that the same pathways that control growth of embryonic cells also govern regeneration of adult tissue. In the lung, several mutant phenotypes have revealed that the Wnt pathway is required for lung development, but its function in adult tissues is not well understood. We have examined the activation of Wnt signaling in adult lungs using different Wnt reporter mice, in which signaling can be visualized in vivo. These reporter lines reveal Wnt signaling in Clara cells, suggesting that Wnts may play a role in Clara cell formation or maintenance.

Our research also uses the fruitfly Drosophila as a model system, where we can use the genetics of this organism as a tool. We have also isolated and characterized mutations in several Wnt genes in Drosophila. Interestingly, we found that one of these Wnts, WntD, interacts with another highly conserved signaling pathway, the Toll-NfκB pathway. This pathway has numerous functions, including organizing the dorsal-ventral patterning of early fly embryos, but also the regulation of the primary immune response. We found that over-expression of WntD produces dorsalized embryos that completely lack ventral tissues due to a block in Toll- NfκB signaling. Furthermore, while WntD loss-of-function mutants, created with gene targeting technology, are viable, mutant embryos show a mild expansion of nuclear NfκB into regions where WntD is normally present. Taken together, these data suggest that WntD plays a role in restricting the special and temporal activation of Toll- NfκB signaling during early embryogenesis. In addition to its role in embryogenesis, Toll signaling plays a crucial role in mediating both the humoral and cellular responses of the Drosophila innate immune system.