Chronic wounds are a common and debilitating complication for the diabetic population. It is challenging to study the development of chronic wounds in human patients; by the time it is clear that a wound is chronic, the early phases of wound healing have passed and can no longer be studied. Because of this limitation, mouse models have been employed to better understand the early phases of chronic wound formation. In the past few years, a series of reports have highlighted the importance of reactive oxygen species and bacterial biofilms in the development of chronic wounds in diabetics. We review these recent findings and discuss mouse models that are being utilized to enhance our understanding of these potentially important contributors to chronic wound formation in diabetic patients.

In Drosophila melanogaster, the loss of activator de2f1 leads to a severe reduction in cell proliferation and repression of E2F targets. To date, the only known way to rescue the proliferation block in de2f1 mutants was through the inactivation of dE2F2. This suggests that dE2F2 provides a major contribution to the de2f1 mutant phenotype. Here, we report that in mosaic animals, in addition to de2f2, the loss of a DEAD box protein Belle (Bel) also rescues proliferation of de2f1 mutant cells. Surprisingly, the rescue occurs in a dE2F2-independent manner since the loss of Bel does not relieve dE2F2-mediated repression. In the eye disc, bel mutant cells fail to undergo a G 1 arrest in the morphogenetic furrow, delay photoreceptor recruitment and differentiation, and show a reduction of the transcription factor Ci155. The down-regulation of Ci155 is important since it is sufficient to partially rescue proliferation of de2f1 mutant cells. Thus, mutation of bel relieves the dE2F2-mediated cell cycle arrest in de2f1 mutant cells through a novel Ci155-dependent mechanism without functional inactivation of the dE2F2 repressor.Cell proliferation and differentiation are precisely coordinated during the development of a multicellular organism. The loss of such control may ultimately lead to defects in development and cancer. E2F transcription factors are important regulators of the cell cycle and critical downstream targets of the retinoblastoma (pRB) tumor suppressor protein (12). In spite of remarkable progress, dissecting the pRB pathway in mammalian cells remains a challenging task. One issue arises from functional redundancy and compensation among E2F and pRB family members. In the past years, Drosophila melanogaster has been recognized as a valuable tool for understanding various aspects of E2F biology. This is mainly due to the high conservation in cell cycle regulation between flies and mammals and the relative simplicity of the E2F/pRB module in Drosophila. In Drosophila, there are two E2F genes. As mammalian counterparts, their products can be classified as repressors (dE2F2) and activators (dE2F1).Analysis of dE2F single-and double-mutant animals has provided insights into the normal function of dE2Fs during development. de2f1 mutant larva are severely retarded in larval growth and show a strong reduction in S phases and the expression of E2F targets. Unexpectedly, these defects are largely suppressed in de2f1 de2f2 double mutants. This suggests that the de2f1 mutant phenotype is not entirely due to the absence of activator dE2F1 but rather, to some extent, is due to the presence of the "unchecked" repressor dE2F2 (18). This result is particularly striking since de2f2 mutants are viable and develop normally (5, 18). Why "unchecked" dE2F2 has such a strong effect on cell proliferation in the absence of dE2F1 is not clear. A possible explanation, supported by gene expression profiling (11), is that, in de2f1 mutant cells, dE2F2 inappropriately represses dE2F1-specific genes that are critical for cell proliferation. ...

SUMMARY E2F/DP transcription factors regulate cell proliferation and apoptosis. Here, we investigated the mechanism of the resistance of Drosophilad DP mutants to irradiation-induced apoptosis. Contrary to the prevailing view, this is not due to an inability to induce the apoptotic transcriptional program, since we show that this program is induced, but rather due to a mitochondrial dysfunction of dDP mutants. We attribute this defect to E2F/DP-dependent control of expression of mitochondria associated genes. Genetic attenuation of several of these E2F/DP targets mimics the dDP mutant mitochondrial phenotype and protects from irradiation-induced apoptosis. Significantly, the role of E2F/DP in the regulation of mitochondrial function is conserved between flies and humans. Thus, our results uncovered a role of E2F/DP in the regulation of mitochondrial function and demonstrate that this aspect of E2F regulation is critical for the normal induction of apoptosis in response to irradiation.

BackgroundIn response to a wound, fibroblasts are activated to migrate toward the wound, to proliferate and to contribute to the wound healing process. We hypothesize that changes in pre-mRNA processing occurring as fibroblasts enter the proliferative cell cycle are also important for promoting their migration.ResultsRNA sequencing of fibroblasts induced into quiescence by contact inhibition reveals downregulation of genes involved in mRNA processing, including splicing and cleavage and polyadenylation factors. These genes also show differential exon use, especially increased intron retention in quiescent fibroblasts compared to proliferating fibroblasts. Mapping the 3′ ends of transcripts reveals that longer transcripts from distal polyadenylation sites are more prevalent in quiescent fibroblasts and are associated with increased expression and transcript stabilization based on genome-wide transcript decay analysis. Analysis of dermal excisional wounds in mice reveals that proliferating cells adjacent to wounds express higher levels of cleavage and polyadenylation factors than quiescent fibroblasts in unwounded skin. Quiescent fibroblasts contain reduced levels of the cleavage and polyadenylation factor CstF-64. CstF-64 knockdown recapitulates changes in isoform selection and gene expression associated with quiescence, and results in slower migration.ConclusionsOur findings support cleavage and polyadenylation factors as a link between cellular proliferation state and migration.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1551-9) contains supplementary material, which is available to authorized users.

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