A Drosophila model for fibrodysplasia ossificans progressiva (FOP) (original) (raw)

Drosophila models of FOP provide mechanistic insight

Bone, 2017

Fibrodysplasia ossificans progressiva (FOP) is a rare bone disease characterized by episodic events of heterotopic ossification (HO). All cases of FOP have been attributed to mutations in the ACVR1 gene that render the encoded BMP type I ALK2 receptor hypersensitive, resulting in the activation of BMP signaling, at inappropriate times in inappropriate locations. The episodic or sporadic nature of HO associated with FOP rests with the occurrence of specific 'triggers' that push the hypersensitive ALK2-FOP receptor into full signaling mode. Identification of these triggers and their mechanism of action is critical for preventing HO and its devastating consequences in FOP patients. Models of FOP, generated in Drosophila, are shown to activate the highly conserved BMP signaling pathway in both Drosophila cell culture and in developing tissues in vivo. The most common FOP mutation, R206H, in ALK2 and its synonymous mutation, K262H, in the orthologous Drosophila receptor Sax, abol...

The role of the mfl/Nop60b Drosophila gene in tissue homeostasis and cell- proliferation

2015

The Drosophila mfl/Nop60b gene belongs to a highly conserved family whose members encode the ubiquitous pseudouridine synthase component of H/ACA snoRNPs. These nucleolar complexes are involved in essential cellular processes, such as ribosome biogenesis and RNA pseudouridylation. Loss of function mutations of the mfl/Nop60b human orthologue cause X-linked Dyskeratosis congenita, a multisystemic syndrome accompanied by telomerase defects, premature aging, stem cell dysfunction and increased cancer susceptibility. The striking conservation of snoRNP functions, coupled with a highly divergent mechanism of telomere elongation, makes Drosophila an ideal animal model in which to assess non-telomerasic functions of eukaryotic pseudouridine synthases. Since Drosophila imaginal wing discs represent an ideal system to investigate cell death, proliferation and patterning, I focused on the effects triggered by mfl-slencing in this tissue. Here I show that localized depletion of Mfl protein in ...

Systematic Analysis and Model of Fibroblast Senescence Transcriptome

Cell senescence is a diverse phenotype and therapies often require combinatorial approaches. Here we have systematically collected transcriptomic data related to human fibroblasts to a total of 98 studies. We formed a database describing the relevant variables for each study which we have hosted online allowing users to filter the studies to select variables and genes of interest. Our own analysis of the database revealed 13 marker genes consistently downregulated in senescent cells compared to proliferating controls; however, we also found gene expression patterns that were highly specific and reliable for different senescence inducers, cell lines, and timepoint after induction, confirming several conclusions of existing studies based on single datasets, including differences in p53 and inflammatory signals between oncogene induced senescence (OIS) and DNA damage induced senescence (DDIS). We saw little evidence of an initial TGF-β-centric SASP, but we did find evidence of a decrea...

Profiling of Y1 Cells Treated with FGF-2 Reveals Parallels with Oncogene-Induced Senescence

2020

ABSTRACTParadoxically, oncogenes that drive cell cycle progression may also trigger pathways leading to senescence, thereby inhibiting the growth of tumorigenic cells. Along these lines, Y1 cells, which carry an amplification of Ras, become senescent after treatment with the mitogen FGF-2. To understand how FGF-2 promotes senescence, we profiled the epigenome, transcriptome, proteome, and phospho-proteome of Y1 cells stimulated with FGF-2. FGF-2 caused delayed acetylation of histone H4 and higher levels of H3K27me3. Sequencing analysis revealed decreased expression of cell cycle-related genes with concomitant loss of H3K27ac. In contrast, FGF-2 promoted the expression of p21, various cytokines, and MAPK-related genes. Nuclear envelope proteins, particularly lamin B1, displayed increased phosphorylation in response to FGF-2. Proteome analysis suggested alterations in cellular metabolism, as evident by modulated expression of enzymes involved in purine biosynthesis, tRNA aminoacylatio...