Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation

•Plasma cells and effector T cells are produced during an asymmetric cell division•Production of differentiated lymphocytes is coupled to renewal of the progenitor cell•Unequal PI3K signaling during cell division bifurcates sibling fates•Unequal PI3K/AKT/mTOR intensity causes unequal FoxO1 inactivation in sibling cells

SummaryMetazoan sibling cells often diverge in activity and identity, suggesting links between growth signals and cell fate. We show that unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling during cell division bifurcates transcriptional networks and fates of kindred cells. A sibling B lymphocyte with stronger signaling, indexed by FoxO1 inactivation and IRF4 induction, undergoes PI3K-driven Pax5 repression and plasma cell determination, while its sibling with weaker PI3K activity renews a memory or germinal center B cell fate. PI3K-driven effector T cell determination silences TCF1 in one sibling cell, while its PI3K-attenuated sibling self-renews in tandem. Prior to bifurcations achieving irreversible plasma or effector cell fate determination, asymmetric signaling during initial divisions specifies a more proliferative, differentiation-prone lymphocyte in tandem with a more quiescent memory cell sibling. By triggering cell division but transmitting unequal intensity between sibling cells, nutrient-sensitive signaling may be a frequent arbiter of cell fate bifurcations during development and repair.

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