Arid1a regulates cell cycle exit of transit-amplifying cells by inhibiting the Aurka-Cdk1 axis in mouse incisor

Abstract

Stem cells self-renew or give rise to transit-amplifying cells (TACs) that differentiate into specific functional cell types. The fate determination of stem cells to TACs and their transition to fully differentiated progeny are precisely regulated to maintain tissue homeostasis. Arid1a, a core component of the switch/sucrose nonfermentable (SWI/SNF) complex, performs epigenetic regulation of stage- and tissue-specific genes that is indispensable for stem cell homeostasis and differentiation. However, the functional mechanism of Arid1a in the fate commitment of mesenchymal stem cells (MSCs) and their progeny is not clear. Using the continuously growing adult mouse incisor model, we show that Arid1a maintains tissue homeostasis through limiting proliferation, promoting cell cycle exit and differentiation of TACs by inhibiting the Aurka-Cdk1 axis. Loss of Arid1a overactivates the Aurka-Cdk1 axis, leading to expansion of the mitotic TAC population but compromising their differentiation ability. Furthermore, the defective homeostasis after loss of Arid1a ultimately leads to reduction of the MSC population. These findings reveal the functional significance of Arid1a in regulating the fate of TACs and their interaction with MSCs to maintain tissue homeostasis.

Genetic Mechanism Study of Auditory Phoenix Spheres and Transcription Factors Prediction for Direct Reprogramming by Bioinformatics

“…In the signalling cascade, Aurka is the regulator at the very upstream and activates Plk1 (non-hub gene, in cluster 1) through phosphorylation, which is regulated by a series of events, and eventually activates the effector Cdk1 via dephosphorylation [ 45 ]. Previous studies show that the Aurka-Cdk1 axis is a part of a feedback activation loop at mitosis entry and its activity peaks during mitosis and mitotic exit [ 46 , 47 , 48 ]. Based on above evidence, the phoenix spheres may belong to the TACs population, hence exhibit active mitosis with involvement of the Aurka-Cdk1 axis.…”

Rodent incisor as a model to study mesenchymal stem cells in tissue homeostasis and repair

“…Our study has also shown that MSCs in the proximal region of the adult incisor take about four weeks to populate the entire dental mesenchyme and reach the distal end of the incisor (19). This knowledge has provided the opportunity to measure the rate by which MSCs give rise to cells of the incisor mesenchyme, such as odontoblasts and dental pulp cells, which has facilitated the analysis of how genetic mutations, for example, may affect the migration of MSC progeny and ultimately affect the fate of these cells in supporting tissue homeostasis and repair (27,28). Similarly, the rate of odontoblast differentiation from the MSCs/TACs can also be measured.…”

“…Finally, because of the easy access to and well defined molecular markers in adult mouse incisors, we can measure the growth rate of the incisor and its ability to repair following injury. These analyses can be linked with the dynamic changes in MSCs or TACs in the proximal region of the incisor, making it possible to comprehensively evaluate the molecular and cellular processes involved in tissue homeostasis and repair (27,28).…”

“…A recent study found that Arid1a, the largest subunit in the BAF complex, regulates mouse incisor tissue homeostasis through controlling proliferation of TACs and promoting cell cycle exit by inhibiting the Aurka-Cdk1 axis. After loss of Arid1a, the mitotic TAC population was expanded along and TAC differentiation was compromised (28).…”

“…Transit amplifying cells are important intermediates between stem cells and their progeny (18). Although several studies using the mouse incisor have investigated the contribution of TACs to homeostasis, their function as a niche component is yet to be determined (28,29,37,91). Interestingly, Amnon et al found that a group of cycling epithelial progenitors can give rise to ameloblasts and adjacent layers of non-ameloblast cells, highlighting the importance of actively proliferating cells contributing to homeostasis and injury repair (26).…”