The Secondary Crest Myofibroblast PDGFRa Controls Elastogenesis Pathway via a Secondary Tier of Signaling Networks During Alveogenesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE126457 | GEO | 2019/02/13
REPOSITORIES: GEO
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Project description:The Secondary Crest Myofibroblast PDGFRa Controls Elastogenesis Pathway via a Secondary Tier of Signaling Networks During Alveogenesis
| PRJNA521967 | ENA
Project description:Signaling through the platelet-derived growth factor receptor alpha (PDGFRa) plays a critical role in craniofacial development, as mutations in PDGFRA are associated with cleft lip/palate in humans and Pdgfra mutant mouse models display varying degrees of facial clefting. Phosphatidylinositol 3-kinase (PI3K)/Akt is the primary effector of PDGFRa signaling during skeletal development in the mouse. We previously demonstrated that Akt phosphorylates the RNA-binding protein serine/arginine-rich splicing factor 3 (Srsf3) downstream of PI3K-mediated PDGFRa signaling in mouse embryonic palatal mesenchyme (MEPM) cells, leading to its nuclear translocation. We further showed that ablation of Srsf3 in the murine neural crest lineage results in severe midline facial clefting, due to defects in proliferation and survival of cranial neural crest cells, and widespread alternative RNA splicing (AS) changes. Here, we sought to determine the molecular mechanisms by which Srsf3 activity is regulated downstream of PDGFRa signaling to control AS of transcripts necessary for craniofacial development. We demonstrated via enhanced UV-crosslinking and immunoprecipitation (eCLIP) of MEPM cells that PDGF-AA stimulation leads to preferential binding of Srsf3 to exons and loss of binding to canonical Srsf3 CA-rich motifs. Through the analysis of complementary RNA-seq data, we showed that Srsf3 activity results in the preferential inclusion of exons with increased GC content and lower intron to exon length ratio. Moreover, we found that the subset of transcripts that are bound by Srsf3 and undergo AS upon PDGFRa signaling commonly encode regulators of PI3K signaling and early endosomal trafficking. Functional validation studies further confirmed that Srsf3 activity downstream of PDGFRa signaling leads to retention of the receptor in early endosomes and increases in downstream PI3K-mediated Akt signaling. Taken together, our findings reveal that growth factor-mediated phosphorylation of an RNA-binding protein underlies gene expression regulation necessary for mammalian craniofacial development.
2024-05-02 | GSE263168 | GEO
Project description:Signaling through the platelet-derived growth factor receptor alpha (PDGFRa) plays a critical role in craniofacial development, as mutations in PDGFRA are associated with cleft lip/palate in humans and Pdgfra mutant mouse models display varying degrees of facial clefting. Phosphatidylinositol 3-kinase (PI3K)/Akt is the primary effector of PDGFRa signaling during skeletal development in the mouse. We previously demonstrated that Akt phosphorylates the RNA-binding protein serine/arginine-rich splicing factor 3 (Srsf3) downstream of PI3K-mediated PDGFRa signaling in mouse embryonic palatal mesenchyme (MEPM) cells, leading to its nuclear translocation. We further showed that ablation of Srsf3 in the murine neural crest lineage results in severe midline facial clefting, due to defects in proliferation and survival of cranial neural crest cells, and widespread alternative RNA splicing (AS) changes. Here, we sought to determine the molecular mechanisms by which Srsf3 activity is regulated downstream of PDGFRa signaling to control AS of transcripts necessary for craniofacial development. We demonstrated via enhanced UV-crosslinking and immunoprecipitation (eCLIP) of MEPM cells that PDGF-AA stimulation leads to preferential binding of Srsf3 to exons and loss of binding to canonical Srsf3 CA-rich motifs. Through the analysis of complementary RNA-seq data, we showed that Srsf3 activity results in the preferential inclusion of exons with increased GC content and lower intron to exon length ratio. Moreover, we found that the subset of transcripts that are bound by Srsf3 and undergo AS upon PDGFRa signaling commonly encode regulators of PI3K signaling and early endosomal trafficking. Functional validation studies further confirmed that Srsf3 activity downstream of PDGFRa signaling leads to retention of the receptor in early endosomes and increases in downstream PI3K-mediated Akt signaling. Taken together, our findings reveal that growth factor-mediated phosphorylation of an RNA-binding protein underlies gene expression regulation necessary for mammalian craniofacial development.
2024-05-02 | GSE263169 | GEO
Project description:The adult lung alveolus is a flexible 3D structure composed of multiple epithelial, endothelial, and mesenchymal cell types. Two highly specialized alveolar type I (AT1) and type II (AT2) cells, derived from epithelial progenitors, form the inner lining of the alveolus. During alveologenesis, the increasing demand for epithelial cells to cover the surface of the expansive number of alveoli is met by proliferating progenitor cells. There is presently little information about the identity of this population, and the niche microenvironment that controls its proliferation. We show that during alveologenesis genetic inactivation of TGFreceptors in hedgehog-responsive, PDGFRa(+) mesodermal cells previously identified as secondary crest myofibroblasts or SCMF reduces their number, and depletes a unique pool of proliferative epithelial progenitors, without significantly impacting differentiation of cells existing the pool. SCMF are a source of both extracellular matrix and secreted trophic molecules and may thus constitute a key component of the epithelial progenitor niche during alveologenesis. Paralleling the mouse model, we found evidence of reduced proliferation of SFTPC(+) progenitors in lungs of human preterm infants who died with bronchopulmonary dysplasia or BPD. SCMF are a transient cell population, which are depleted at completion of alveologenesis, making them a unique stage-dependent niche mesodermal cell type in mammalian organs.
2021-04-15 | GSE172059 | GEO
Project description:Context: Gastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5–7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is corre-lated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different bio-logical behavior of this GIST subset.
2022-10-31 | GSE215402 | GEO
Project description:PDGFRa+ matrix and myofibroblasts decrease and PDGFRa+ lipofibroblasts increase during hyperoxia injury at both a transcriptional and population level.
2021-11-03 | GSE171812 | GEO
Project description:PDGFRA-expressing mesenchyme supports intestinal stem cells. Stomach epithelia have related niche dependencies, but their enabling mesenchymal cell populations are unknown, in part because previous studies pooled the gastric antrum and corpus. Our high-resolution imaging, transcriptional profiling, and organoid assays identified regional subpopulations and supportive capacities of purified mouse corpus and antral PDGFRA+ cells. Sub-epithelial PDGFRAHi myofibroblasts are principal sources of BMP ligands and two molecularly distinct pools distribute asymmetrically along antral glands but together fail to support epithelial growth in vitro. In contrast, PDGFRALo CD55+ cells strategically positioned beneath gastric glands promote epithelial expansion in the absence of other cells or factors. This population encompasses a small fraction expressing the BMP antagonist Grem1. Although Grem1+ cell ablation in vivo impairs intestinal stem cells, gastric stem cells are spared, implying that CD55+ cell activity in epithelial self-renewal derives from other subpopulations. Our findings shed light on spatial, molecular, and functional organization of gastric mesenchyme and the spectrum of signaling sources for epithelial support.
2023-10-29 | GSE224737 | GEO
Project description:Mouse hematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5) on the ventral surface of the dorsal aorta, by endothelial-to-hematopoietic transition (EHT). We investigated whether cells with mesenchymal stem cell-like cell (MSC-LCs) activity that provide an essential niche for HSCs in the bone marrow reside in the aorta-gonad-mesonephros (AGM) and contribute to the structural development of the dorsal aorta and EHT. Using transgenic mice, we demonstrate a lineage hierarchy for AGM MSC-LCs and trace the aortic endothelium and HSCs to mesoderm-derived (Mesp1) PDGFRA+ cells. Mesp1/PDGFRA+ MSC-LCs dominate the sub-endothelial and ventral stroma in the E10.5–E11.5 AGM but by E13.5 are replaced by neural crest (Wnt1) MSC-LCs. Co-aggregating endothelial cells with Mesp1 but not with Wnt1 MSC-LCs resulted in EHT and generation of LT-HSCs that is interrupted by dose-dependent inhibition of PDGFRA signalling. This partnership between endothelial cells and AGM Mesp1 MSC-LCs could be harnessed to manufacture HSCs from endothelium.
2022-04-26 | GSE163757 | GEO
Project description:During embryonic development, the first hematopoietic stem cells (HSCs) arise from a transient population of endothelial cells lining the ventral surface of the dorsal aorta, via a process of endothelial to hematopoietic transition (EHT) at embryonic day (E) 10.5. This region contains resident PDGFRA+ stromal cells (PSCs), but their identity and role in HSC generation in the AGM are not well understood. Using a library of compound transgenic mice, we identified a population of PDGFRA+/Nestin-GFP (N-GFP)-/PDGFRB-/CD31- cells with PSC activity in the E10.5 and E11.5 mouse AGM. Freshly isolated PSCs were adept at forming blood vessels with CD31+ luminal endothelium enveloped by PDGFRB+ pericytes, when transplanted subcutaneously into mice. Conditional ablation of PDGFRA+ or Nestin+ cells led to either complete or partial loss of PSCs respectively, with severe loss of endothelial and pericyte-like cells, and concomitant loss of blood formation in the AGM. Lineage tracing studies using tamoxifen induction in PDGFRACreERT2/R26eYFP embryos showed that stromal, sub-endothelial, endothelial and long-term repopulating hematopoietic stem cells (LT-HSCs) cells in the E11.5 AGM were progeny of PDGFRA cells. Using transgenic reporter mice, we showed that MesP1 (mesoderm) derived PDGFRA+ cells dominated the sub-endothelial and deeper ventral stroma in the AGM at E10.5 and E11.5 but were replaced by Wnt1 (neural crest) derived cells at E13.5. Re-aggregation of E11.5 Mesp1 derived PSC cells with E13.5 aortic or adult cardiac non-hemogenic endothelial cells resulted in the generation of endothelial cell derived LT-HSCs. RNA-sequencing analysis of non-hemogenic E13.5 endothelial cells showed up-regulation of EHT genes, WNT, BMP and Notch cell signalling pathways when re-aggregated with E11.5 Mesp1 derived PSCs. LT-HSC generation from these re-aggregates was suppressed by dose-dependent inhibition of PDGF-AA/PDGFRA signalling. Taken together, we report that PSC populations in the AGM are temporally dynamic, and that MesP1-derived PSCs regulate hemogenic potential of the endothelium and that this cooperativity is dependent on PDGF-AA/PDGFRA signalling. This submission represents the RNAseq component of the study.
2022-04-26 | GSE114464 | GEO
Project description:Analysis of Nestin-GFP+ pericytes flow sorted from 3-day-old mouse cutaneous adipose tissue, comparing controls with wild type PDGFRa, and mutants with increased PDGFRa signaling driven by a Cre/lox-inducible D842V knockin mutation in the PDGFRa kinase domain. The control cells have adipogenic properties in vitro or when transplanted subcutaneously into recipient mice. The D842V mutant cells show altered behavior in the same assays, with poor adipogenic differentiation but a propensity to transition into profibrotic cells that secrete collagen
2015-06-01 | GSE64510 | GEO