The Rho GTPase exchange factor Vav2 promotes extensive age-dependent rewiring of the skin stem cell transcriptome

Abstract

ABSTRACTBoth the number and regenerative activity of skin stem cells (SSCs) are regulated by Vav2, a GDP/GTP exchange factor involved in the catalytic stimulation of the GTPases Rac1 and RhoA. However, whether Vav2 signaling changes in SSCs over the mouse lifespan is not yet known. Using a mouse knock-in mouse model, we now show that the expression of a catalytically-active version of Vav2 (Vav2Onc) promotes an extensive rewiring of the overall transcriptome of SSCs, the generation of new transcription factor hubs, and the synchronization of many transcriptional programs associated with specific SSC states and well-defined signaling pathways. Interestingly, this transcriptome rewiring is not fixed in time, as it involves the induction of 15 gene expression waves with diverse distribution patterns during the life of the animals. These expression waves are consistent with the promotion by Vav2Onc of several functional SSC states that differ from those normally observed in wild-type SSCs. These results further underscore the role of Vav2 in the regulation of the functional state of SSCs. They also indicate that, unlike other Vav2-dependent biological processes, the signaling output of this exchange factor is highly contingent on age-dependent intrinsic and/or extrinsic SSC factors that shape the final biological readouts triggered in this cell type.AUTHOR SUMMARYSkin stem cells (SSCs) are essential for the homeostatic balance of the skin, yet little is known to date about the biological and molecular mechanisms that modulate their abundance, long-term stability, or functional states during ageing. To address this issue, in this work we have used a genetically-engineered gain-of-function mouse model for Vav2, a Rho guanine nucleotide exchange factor (GEF) that has been recently shown to be involved in skin stem cell homeostasis. By performing time-course genome-wide expression analyses combined with a number of computational methods, here we show that: (i) Vav2 plays a critical role in regulating the functional state of SSCs, and (ii) the signaling output of constitutively active Vav2 is highly contingent on age-dependent intrinsic and/or extrinsic SSC factors that shape the final biological readouts triggered in this cell type. We believe that these data represent, to our knowledge, one of the first examples of the time-dependent output of an oncogenic version of a Rho GEF along a wide time interval in mice.