Abstract
Cyclin Y family can enhance Wnt/β-catenin signaling in mitosis. Their physiological roles in mammalian development are yet unknown. Here we show that Cyclin Y-like 1 (Ccnyl1) and Cyclin Y (Ccny) have overlapping function and are crucial for mouse embryonic development and mammary stem/progenitor cell functions. Double knockout of Ccnys results in embryonic lethality at E16.5. In pubertal development, mammary terminal end buds robustly express Ccnyl1. Depletion of Ccnys leads to reduction of Lrp6 phosphorylation, hampering β-catenin activities and abolishing mammary stem/progenitor cell expansion in vitro. In lineage tracing experiments, Ccnys-deficient mammary cells lose their competitiveness and cease to contribute to mammary development. In transplantation assays, Ccnys-deficient mammary cells fail to reconstitute, whereas constitutively active β-catenin restores their regeneration abilities. Together, our results demonstrate the physiological significance of Ccnys-mediated mitotic Wnt signaling in embryonic development and mammary stem/progenitor cells, and reveal insights in the molecular mechanisms orchestrating cell cycle progression and maintenance of stem cell properties.
Highlights
Stem cell self-renewal is tightly associated with cell cycle progression
The interconnections between cell cycle and cell fate specification have been explored in embryonic stem cells
Less is known about how cell cycle affects the cell fate decision in tissue stem cells
Summary
Stem cell self-renewal is tightly associated with cell cycle progression. In particular, active stem cells rapidly divide and coordinate with cell fate choices [1]. Wnt/β-catenin signaling plays a prominent role in adult stem cell self-renewal in many tissues [3]. The level of Wnt/β-catenin signaling in stem cells is meticulously regulated, while different activation levels of the signaling result in distinct fate decisions by stem cells [4,5,6]. A key step for stoichiometric regulation of Wnt signaling happens at the membrane, where Lrp receptor activation occurs in sequential steps before reaching its full competence. The finding of Lrp phosphorylation by Ccny/ Cdk reveals a cell cycle dependent Wnt signaling activation mechanism, adding a new level of complexity to stoichiometric Wnt signaling activation [9,11]. Enhancing the Wntreceptor Lrp competence by Ccny is important for Xenopus development [9], whether a similar Ccny/Lrp regulatory event is physiologically significant in mammals and in stem cell biology is unknown
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