title: Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Wen-Hsuan W
authors.initials: WH
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Adams
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Nish
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Yen
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Nyanza J
authors.initials: NJ
authors.lastname: Rothman
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Radomir
authors.initials: R
authors.lastname: Kratchmarov
authors.affiliation: Laboratory for Tissue Dynamics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Pathology and Cell Biology and Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: sr2978@cumc.columbia.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010950:Plasma Cells / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019869:Phosphatidylinositol 3-Kinases