Grainger Laboratory

Wnt Signaling in Hematopoietic Stem Cell Development and Cancer

If the human body is an ongoing construction project, then stem cells are its all-purpose building materials. These biological “blank slates” give rise to all the specialized cell types needed to assemble and power the human body, from skin cells to heart cells and everything in between. Understanding how stem cells develop and what happens when the signals guiding them go wrong can reveal how diseases arise and point toward new treatments.

The Grainger Lab studies the signals that control stem cell development, with a particular focus on hematopoietic stem cells (HSCs), which give rise to the blood and immune systems. Our work has shown that the Wnt ligand Wnt9a helps amplify emerging HSCs earlier in development than previously recognized (Grainger, Richter et al., 2016). We later found that Wnt9a signals through the Frizzled receptor Fzd9b, with EGFR helping to confer signaling specificity (Grainger et al., 2019).

We now are working to learn more about this signaling axis, as well as other Wnt signals. Using zebrafish and cell culture, we are exploring how signals from surrounding tissues help establish the developmental environment in which HSCs form. For example, we found that EGFR-dependent phosphorylation helps drive Wnt9a–Fzd9b internalization, which depends on caveolin and the scaffolding protein EPS15 and is needed for HSC development (Nguyen et al., 2024). We also found that the ubiquitin ligase TRIP12 modifies Fzd9b, promoting its removal and reducing Wnt9a–Fzd9b signaling and HSC proliferation (Ensing et al., 2025). Together, these studies reveal how receptor activation, trafficking and turnover help tune Wnt signals during blood development.

Our research extends beyond Wnt signaling to other pathways that shape development and disease. In a recent study, we used zebrafish to model developmental defects associated with NAD⁺ deficiency, including heart, spinal, tail and craniofacial abnormalities (Tsurho et al., 2025). We also are developing a zebrafish model of Bachmann–Bupp syndrome, a rare disorder caused by ODC1 variants that increase enzyme activity and disrupt polyamine balance. This work explores how altered metabolism affects development and may provide a platform for studying rare diseases.

To study cancer, we use zebrafish models to investigate how developmental signals and cancer-driving changes affect blood-forming cells. This includes work on KMT2A::MLLT3 leukemia, where we can examine how cells respond when the leukemia-driving signal is turned on and off.