Wnt signaling couples G2 phase control with differentiation during hematopoiesis in Drosophila

During homeostasis, a critical balance is maintained between myeloid-like progenitors and their differentiated progeny, which function to mitigate stress and innate immune challenges. The molecular mechanisms that help achieve this balance are not fully understood. Using genetic dissection in Drosophila, we show that a Wnt6/EGFR-signaling network simultaneously controls progenitor growth, proliferation, and differentiation. Unlike G1-quiescence of stem cells, hematopoietic progenitors are blocked in G2 phase by a β-catenin-independent (Wnt/STOP) Wnt6 pathway that restricts Cdc25 nuclear entry and promotes cell growth. Canonical β-catenin-dependent Wnt6 signaling is spatially confined to mature progenitors through localized activation of the tyrosine kinases EGFR and Abelson kinase (Abl), which promote nuclear entry of β-catenin and facilitate exit from G2. This strategy combines transcription-dependent and -independent forms of both Wnt6 and EGFR pathways to create a direct link between cell-cycle control and differentiation. This unique combinatorial strategy employing conserved components may underlie homeostatic balance and stress response in mammalian hematopoiesis. [Display omitted] •Hematopoietic progenitors pause in the G2 phase by cytoplasmic sequestration of Cdc25•A Wnt6-dependent, but β-catenin-independent, pathway enforces the G2 pause•A Hedgehog signal from the niche controls Wnt6 transcription in the progenitors•RTK activity in mature progenitors activates β-catenin, via Abl, which promotes G2 exit In this manuscript, Goins et al. provide a molecular mechanism that directly links the cell cycle and cell fate of blood progenitors through the spatiotemporally concerted action of Hedgehog, Wnt, and EGFR, which combinatorially govern entry into, and exit from, a prolonged G2 phase.