Abstract
Embryonic stem (ES) cells go though embryo-like cell cycles regulated by specialized molecular mechanisms. However, it is not known whether there are ES cell-specific mechanisms regulating mitotic fidelity. Here we showed that Autoimmune Regulator (Aire), a transcription coordinator involved in immune tolerance processes, is a critical spindle-associated protein in mouse ES(mES) cells. BioID analysis showed that AIRE associates with spindle-associated proteins in mES cells. Loss of function analysis revealed that Aire was important for centrosome number regulation and spindle pole integrity specifically in mES cells. We also identified the c-terminal LESLL motif as a critical motif for AIRE's mitotic function. Combined maternal and zygotic knockout further revealed Aire's critical functions for spindle assembly in preimplantation embryos. These results uncovered a previously unappreciated function for Aire and provide new insights into the biology of stem cell proliferation and potential new angles to understand fertility defects in humans carrying Aire mutations.
Highlights
Self-renewal capability, defined as the ability of cells to proliferate while sustaining differentiation potential, is one of the defining features of stem cells (Martello and Smith, 2014)
We report a novel function of the Autoimmune Regulator, Aire, in the mitotic processes of embryonic stem cells and the early embryo
In addition to proteins functioning in general transcription and RNA processing, processes in which Aire was already known to function in somatic cells such as medullary thymic epithelium cells (mTECs) (Abramson et al, 2010; Mathis and Benoist, 2009), we identified many spindle associated proteins
Summary
Self-renewal capability, defined as the ability of cells to proliferate while sustaining differentiation potential, is one of the defining features of stem cells (Martello and Smith, 2014). Unlike in most somatic cells where coordinated fluctuation of Cyclin-CDK activities drive the cells through the cell cycle, ES cells possess higher and constant activity of most Cyclin-CDK pairs except for Cyclin B-CDK1 (Stead et al, 2002). These cell cycle patterns have been proposed to limit the window in which ES cells are responsive to differentiation cues, promoting self-renewal (Dalton, 2015; Pauklin and Vallier, 2013). Given that ES cells show remarkable karyotypic stability, this might suggest that they possess additional specific molecular mechanisms to ensure mitosis fidelity
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