Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation

Cell Rep. 2015 Dec 15;13(10):2203-18. doi: 10.1016/j.celrep.2015.10.072. Epub 2015 Nov 25.


Metazoan 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / physiology*
  • Cell Lineage
  • Flow Cytometry
  • Gene Knock-In Techniques
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Plasma Cells / cytology*
  • Plasma Cells / metabolism
  • Signal Transduction / physiology


  • Phosphatidylinositol 3-Kinases

Associated data

  • GEO/GSE74287