Lin Wen-Hsuan W, Adams William C, Nish Simone A, Chen Yen-Hua, Yen Bonnie, Rothman Nyanza J, Kratchmarov Radomir, Okada Takaharu, Klein Ulf, Reiner Steven L
Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Laboratory for Tissue Dynamics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
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.
后生动物的姐妹细胞在活性和特性上常常会出现差异，这表明生长信号与细胞命运之间存在联系。我们发现，在细胞分裂过程中，营养敏感型PI3K/AKT/mTOR信号的不均等转导会使转录网络和同类细胞的命运发生分歧。信号更强的姐妹B淋巴细胞（以FoxO1失活和IRF4诱导为指标）会经历PI3K驱动的Pax5抑制和浆细胞分化，而其信号较弱的姐妹细胞则会维持记忆或生发中心B细胞的命运。PI3K驱动的效应T细胞分化会使一个姐妹细胞中的TCF1沉默，而其PI3K活性减弱的姐妹细胞则会同步自我更新。在实现不可逆的浆细胞或效应细胞命运决定的分歧之前，初始分裂过程中的不对称信号会指定一个更具增殖性、更易分化的淋巴细胞，同时产生一个更静止的记忆细胞姐妹。通过触发细胞分裂但在姐妹细胞之间传递不等强度的信号，营养敏感型信号可能是发育和修复过程中细胞命运分歧的常见仲裁者。
