Biology subjects

Mondal, B. C.

Publications and source records attributed to Mondal, B. C..

2 recordsLinked to original sources

bioRxiv2023

Macrophage differentiation requires DNA damage caused by Caspase-Activated DNase

Phagocytic macrophages are crucial for innate immunity and tissue homeostasis. Most macrophages develop from embryonic precursors that populate every organ before birth to self-renew lifelong. However, the mechanisms for macrophage differentiation remain unknown. Using in vivo genetic analysis of the Drosophila larval hematopoietic organ, the lymph gland, we show that the developmentally regulated transient activation of Caspase-Activated DNase (CAD)-mediated DNA breaks in intermediate progenitors is essential for macrophage differentiation. Insulin receptor-mediated PI3K/Akt signaling triggers apoptotic signaling and causes DNA breaks during macrophage development. However, the same Akt signaling attenuates Apoptosis signal-regulating kinase 1 (Ask1) to control apoptotic and JNK activity in differentiating macrophages. DNA-damaged differentiating cells display autophagy activity as a survival strategy. Furthermore, caspase activity is required for embryonic-origin macrophage development and efficient phagocytosis. This study reveals a previously unknown relationship between developmental signals and caspase-activated DNA breaks necessary for multifunctional macrophage differentiation.

developmental biology↗

bioRxiv2023

Wnt signaling couples G2 phase control with differentiation during hematopoiesis

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 the G2 phase by a {beta}-catenin-independent Wnt6 pathway that restricts Cdc25 nuclear entry and promotes cell growth. Canonical {beta}-catenin-dependent Wnt6 signaling is spatially confined to mature progenitors through localized activation of the tyrosine-kinases EGFR and Abl, which promote nuclear entry of {beta}-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.

developmental biology↗