Selection on floral traits in hermaphroditic plants is determined by both male and female reproductive success. However, predictions regarding floral trait and mating system evolution are often based solely on female fitness. Selection via male fitness has the potential to affect the outcomes of floral evolution. In this study, we used paternity analysis to assess individual selfing rates and selection on floral traits via male and female fitness in an experimental population of Clarkia xantiana where pollen limitation of seed set was strong. We detected selection through both female and male fitness with reinforcing or noninterfering patterns of selection through the two sex functions. For female fitness, selection favored reduced herkogamy and protandry, traits that promote increased autonomous selfing. For male fitness, selection on petal area was disruptive, with higher trait values conferring greater pollinator attraction and outcross siring success and smaller trait values leading to higher selfed siring success. Combining both female and male fitness, selection on petal area and protandry was disruptive because intermediate phenotypes were less successful as both males and females. Finally, functional relationships among male and female fertility components indicated that selfing resulted in seed discounting and pollen discounting. Under these functional relationships, the evolutionarily stable selfing rate can be intermediate or predominantly selfing or outcrossing, depending on the segregating load of deleterious mutations.
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, incurable blistering skin disease caused by biallelic mutations in type VII collagen (C7). Advancements in treatment of RDEB have come from harnessing the immunomodulatory potential of mesenchymal stem cells (MSCs). Although human bone marrow-derived MSC (BM-MSC) trials in RDEB demonstrate improvement in clinical severity, the mechanisms of MSC migration to and persistence in injured skin and their contributions to wound healing are not completely understood. A unique subset of MSCs expressing ATP-binding cassette subfamily member 5 (ABCB5) resides in the reticular dermis and exhibits similar immunomodulatory characteristics to BM-MSCs. Our work aimed to test the hypothesis that skin-derived ABCB5+ dermal MSCs (DSCs) possess superior skin homing ability compared to BM-MSCs in immunodeficient NOD-scid IL2rgammanull (NSG) mice. Compared to BM-MSCs, peripherally injected ABCB5+ DSCs demonstrated superior homing and engraftment of wounds. Furthermore, ABCB5+ DSCs vs BM-MSCs cocultured with macrophages induced less anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) production. RNA sequencing of ABCB5+ DSCs compared to BM-MSCs showed unique expression of major histocompatibility complex class II and Homeobox (Hox) genes, specifically HOXA3. Critical to inducing migration of endothelial and epithelial cells for wound repair, increased expression of HOXA3 may explain superior skin homing properties of ABCB5+ DSCs. Further discernment of the immunomodulatory mechanisms among MSC populations could have broader regenerative medicine implications beyond RDEB treatment.
Squamous cell carcinoma (SCC) develops in more than 80% of individuals with the skin blistering disorder recessive dystrophic epidermolysis bullosa (RDEB). In contrast with UV‐induced SCC, RDEB‐SCC results from skin damage and has a high proliferative and metastatic rate with 5‐year survival near zero. Our objective is to determine the mechanisms underlying the increased metastatic tendencies of RDEB‐SCC. RDEB‐SCC cultured cell lines were treated with RDEB and non‐RDEB fibroblast conditioned media and assayed for migration and invasion with and without small molecule inhibitors for TGFβ and other downstream signal transduction pathways. TGFβ1 secreted by RDEB dermal fibroblasts has been found to induce migration and invasion and to increase expression of epithelial‐to‐mesenchymal transition markers in an RDEB‐SCC line. These effects were reversed upon inhibition of TGFβ signalling and its downstream pathways MEK/ERK, P38 kinase and SMAD3. A number of small molecule inhibitors for these pathways are in different phases of various clinical trials and may be applicable to RDEB‐SCC patients. Studying the mechanisms of the extreme form RDEB‐SCC may inform studies of other types of SCC, as well as lead to better therapies for RDEB patients.
Epidermolysis bullosa (EB) is a heterogeneous group of genetic skinblistering disorders characterized by increased fragility and impaired structural integrity of the skin. 1 Dystrophic EB (DEB) is a subtype of EB that is exclusively caused by mutations in the COL7A1 gene, which encodes collagen type VII α1 chain. Type VII collagen protein (C7) is formed by the assembly of three proα1(VII) polypeptide chains into a homotrimer. C7 is the main component of anchoring fibrils, which provide mechanical strength and stability to the skin by anchoring the epidermis to the dermis. 2,3 DEB has a wide spectrum of disease severity and can be caused by either dominant (DDEB)
Keratin 17 (K17) is a type I intermediate filament that is highly responsive to stress and inflammation, and occurs in several carcinomas. We previously showed that K17 promotes tumorigenesis in part by impacting the expression of pro-inflammatory and immune response genes when present inside the nucleus. Given the notion that cancer cells exhibit a dysfunctional DNA damage response (DDR), we hypothesized that K17 plays a role in DDR and tumor initiation.Here we assessed the response of tumor epithelial cell lines, skin keratinocytes in culture, Krt17 null and Krt17 DNLS mice (in which K17 lacks a functional nuclear localization signal) to DNA damaging agents including ionizing radiation, X-ray and 7,12-dimethylbenz[a]-anthracene (DMBA). We also assessed the response of mouse skin to two-step chemical carcinogenesis (DMBA,12-O-tetradecanoylphorbol-13-acetate (TPA)). K17 is robustly induced upon DNA damage and after topical treatment with DMBA in mouse skin. The extent of DDR is markedly K17-dependent in all cell culture and mouse models tested, including Krt17 DNLS mice, suggesting that it requires the nuclear-localized form of K17. K17 preferentially impacts the double-stranded DNA breaks (DSBs) arm of DDR signaling cascade. Krt17 null mice develop a reduced number of papilloma in response to DMBA-TPA, correlating with a reduced frequency of oncogenic mutations at the HRas locus. Interestingly, Krt17 DNLS mice do not develop papillomas in this setting. We conclude that the nuclearlocalized form of K17 regulates DDR in keratinocytes and is poised to impact the initiation stage of carcinogenesis in skin. Efforts are under way to define the mechanisms involved, with a particular focus on newly uncovered interactions between K17 and proteins involved in DDR and chromatin architecture.
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