Abstract
Normal long-term repopulating somatic stem cells (SSCs) preferentially divide asymmetrically, with one daughter cell remaining in the niche and the other going on to be a transient amplifying cell required for generating new tissue in homeostatic maintenance and repair processes, whereas cancer stem cells (CSCs) favor symmetric divisions. We have previously proposed that differential β-catenin modulation of transcriptional activity via selective interaction with either the Kat3 coactivator CBP or its closely related paralog p300, regulates symmetric versus asymmetric division in SSCs and CSCs. We have previously demonstrated that SSCs that divide asymmetrically per force retain one of the dividing daughter cells in the stem cell niche, even when treated with specific CBP/β-catenin antagonists, whereas CSCs can be removed from their niche via forced stochastic symmetric differentiative divisions. We now demonstrate that loss of p73 in early corticogenesis biases β-catenin Kat3 coactivator usage and enhances β-catenin/CBP transcription at the expense of β-catenin/p300 transcription. Biased β-catenin coactivator usage has dramatic consequences on the mode of division of neural stem cells (NSCs), but not neurogenic progenitors. The observed increase in symmetric divisions due to enhanced β-catenin/CBP interaction and transcription leads to an immediate increase in NSC symmetric differentiative divisions. Moreover, we demonstrate for the first time that the complex phenotype caused by the loss of p73 can be rescued in utero by treatment with the small-molecule-specific CBP/β-catenin antagonist ICG-001. Taken together, our results demonstrate the causal relationship between the choice of β-catenin Kat3 coactivator and the mode of stem cell division.
Highlights
Adult somatic stem cells (SSCs) ensure homeostatic maintenance and provide regenerative capacity after insult
We demonstrate for the first time that this complex phenotype caused by the KO of p73 can be rescued in utero by treatment with the small-molecule-specific CBP/β-catenin antagonist ICG-001
Normal long-term repopulating somatic stem cells (SSCs) preferentially divide asymmetrically, with one daughter cell remaining in the niche and the other going on to be a transient amplifying cell required to generate new tissue in homeostatic maintenance and repair processes, whereas cancer stem cells (CSCs) favor symmetric divisions
Summary
Adult somatic stem cells (SSCs) ensure homeostatic maintenance and provide regenerative capacity after insult. Long-term repopulating SSCs, generally quiescent, can reenter the cell cycle and subsequently, undergo mitosis. These mitotic divisions can be asymmetric, whereby one of the daughter cells remains in the niche as an SSC, while the other daughter proceeds to differentiate. The decision to undergo an asymmetric versus a symmetric division is critical both during embryogenesis and in the adult organism. Improper regulation of this decision likely underlies a large array of diseases including cancer, neurodevelopmental and neurodegenerative diseases, and more generally, is associated with the aging process [1,2,3,4]
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