Abstract: Runx1/AML1 is a transcription factor implicated in tissue stem cell regulation and belongs to the small Runx family of cancer genes. In the hair follicle (HF), Runx1 epithelial deletion in morphogenesis impairs normal adult hair homeostasis (cycle) and blocks adult hair follicle stem cells (HFSCs) in quiescence. Here, we show that these effects are overcome later in adulthood. By deleting Runx1 after the end of morphogenesis, we demonstrate its direct role in promoting anagen onset and HFSC proliferation. Runx1 deletion resulted in cyclin-dependent kinase inhibitor Cdkn1a (p21) upregulation. Interfering with Runx1 function in cultured HFSCs impaired their proliferation and normal G(0)/G1 and G(1)/S cell cycle progression. The proliferation defect could be rescued by Runx1 readdition or by p21 deletion. Chemically induced skin tumorigenesis in mice turned on broad Runx1 expression in regions of the skin epithelium, papillomas, and squamous cell carcinomas. In addition, it revealed reduced rates of tumor formation in the absence of Runx1 that were accompanied by decreased epithelial levels of phospho-Stat3. Runx1 protein expression was similar in normal human and mouse hair cycles. We propose that Runx1 may act as a skin oncogene by directly promoting proliferation of the epithelial cells.
Notes: Hoi, Lee, Lu, and McDermitt are first co-authors
Abstract: In homeostasis of adult vertebrate tissues, stem cells are thought to self-renew by infrequent and asymmetric divisions that generate another stem cell daughter and a progenitor daughter cell committed to differentiate. This model is based largely on in vivo invertebrate or in vitro mammal studies. Here, we examine the dynamic behavior of adult hair follicle stem cells in their normal setting by employing mice with repressible H2B-GFP expression to track cell divisions and Cre-inducible mice to perform long-term single-cell lineage tracing. We provide direct evidence for the infrequent stem cell division model in intact tissue. Moreover, we find that differentiation of progenitor cells occurs at different times and tissue locations than self-renewal of stem cells. Distinct fates of differentiation or self-renewal are assigned to individual cells in a temporal-spatial manner. We propose that large clusters of tissue stem cells behave as populations whose maintenance involves unidirectional daughter-cell-fate decisions.
Abstract: Aml1/Runx1 controls developmental aspects of several tissues, is a master regulator of blood stem cells, and plays a role in leukemia. However, it is unclear whether it functions in tissue stem cells other than blood. Here, we have investigated the role of Runx1 in mouse hair follicle stem cells by conditional ablation in epithelial cells. Runx1 disruption affects hair follicle stem cell activation, but not their maintenance, proliferation or differentiation potential. Adult mutant mice exhibit impaired de novo production of hair shafts and all temporary hair cell lineages, owing to a prolonged quiescent phase of the first hair cycle. The lag of stem cell activity is reversed by skin injury. Our work suggests a degree of functional overlap in Runx1 regulation of blood and hair follicle stem cells at an equivalent time point in the development of these two tissues.
Abstract: Regulation of stem cell (SC) proliferation is central to tissue homoeostasis, injury repair, and cancer development. Accumulation of replication errors in SCs is limited by either infrequent division and/or by chromosome sorting to retain preferentially the oldest 'immortal' DNA strand. The frequency of SC divisions and the chromosome-sorting phenomenon are difficult to examine accurately with existing methods. To address this question, we developed a strategy to count divisions of hair follicle (HF) SCs over time, and provide the first quantitative proliferation history of a tissue SC during its normal homoeostasis. We uncovered an unexpectedly high cellular turnover in the SC compartment in one round of activation. Our study provides quantitative data in support of the long-standing infrequent SC division model, and shows that HF SCs do not retain the older DNA strands or sort their chromosome. This new ability to count divisions in vivo has relevance for obtaining basic knowledge of tissue kinetics
Abstract: Summary
• Here we conducted a series of 14C pulse-chase labeling experiments to test the hypothesis that ozone reduces allocation of recently assimilated carbon to roots of sugar maple (Acer saccharum).
• Sugar maple seedlings were fumigated with 1.0×, 1.7×and 3.0×ambient ozone in open-top chambers for 3 yr under low and high light. Shoots were labeled with 14CO2 for 1 h in August of year 3, and seedlings were harvested 0, 4, 24 and 48 h after labeling.
• Three years of ozone fumigation reduced total biomass of seedlings in low and high light treatments by 49% and 34%, respectively, and reduced per cent allocation of total seedling biomass to roots. Ozone similarly reduced allocation of net 14C (gross 14CO2 assimilated at time = 0 minus respiratory losses) to roots after 48 h, but not gross14C, despite significant ozone effects on 14CO2 assimilation, leaf-level partitioning, and retention of gross carbon in shoots.
• Although ozone delayed transport of 14C out of leaves initially, it had no effect on the transport process per se. Any reduction in net allocation to roots is most likely a function of changes in whole-plant source–sink relationships, with control a function of both shoot and root traits.
