Wnt signaling out on a limb The Wnt/β-catenin signaling pathway is central to hematopoietic stem cell (HSC) survival, renewal, and differentiation. Both excessive and insufficient β-catenin can have adverse consequences, so “destruction complexes” ensure its precise regulation. Using a mouse forward genetic screen, Choi et al. identified a mutation in the gene limb region 1–like ( Lmbr1l ) that severely impaired lymphocyte development and function. LMBR1L interacted with multiple members of the Wnt/β-catenin signaling pathway. The authors found that LMBR1L works with an endoplasmic reticulum–localized ubiquitin ligase to serve as a second brake on this system in lymphocytes. Deleting β-catenin decreased apoptosis and restored proliferative capacity in an Lmbr1l -deficient mouse T cell line. Science , this issue p. eaau0812