Asymmetric Requirement of Surface Epithelial β-Catenin During the Upper and Lower Jaw Development

Background: Intercellular communication between epithelial and mesenchymal cells is central to mammalian craniofacial development. β-catenin is the gateway of canonical Wnt signaling, one of the major evolutionarily conserved cell–cell communication pathways in metazoa. In this study, we report an unexpected stage- and tissue-specific function of β-catenin during mammalian jaw development. Results: Using a unique mouse genetic tool, we have discovered that epithelial β-catenin is essential for lower jaw formation, while attenuation of β-catenin is required for proper upper jaw development. Changes in β-catenin in vivo alter major epithelial Fgf8, Bmp4, Shh, and Edn1 signals, resulting in partial transcriptional reprogramming of the neural crest-derived mesenchyme, the primary source of jawbones. Conclusions: The Wnt/β-catenin signal coordinates expression of multiple epithelial signals and has stage-specific asymmetric functions during mammalian upper and lower jaw development. In addition, these findings suggest that evolutionary changes of the canonical Wnt/β-catenin signaling pathway may lead to innovation of jaws

PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity

Fibrosis is a common disease process in which profibrotic cells disturb organ function by secreting disorganized extracellular matrix (ECM). Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction, but how profibrotic cells originate is still being elucidated. Here, we use a developmental model to investigate perivascular cells in white adipose tissue (WAT) and their potential to cause organ fibrosis. We show that a Nestin-Cre transgene targets perivascular cells (adventitial cells and pericyte-like cells) in WAT, and Nestin-GFP specifically labels pericyte-like cells. Activation of PDGFRα signaling in perivascular cells causes them to transition into ECM-synthesizing profibrotic cells. Before this transition occurs, PDGFRα signaling up-regulates mTOR signaling and ribosome biogenesis pathways and perturbs the expression of a network of epigenetically imprinted genes that have been implicated in cell growth and tissue homeostasis. Isolated Nestin-GFP+ cells differentiate into adipocytes ex vivo and form WAT when transplanted into recipient mice. However, PDGFRα signaling opposes adipogenesis and generates profibrotic cells instead, which leads to fibrotic WAT in transplant experiments. These results identify perivascular cells as fibro/adipogenic progenitors in WAT and show that PDGFRα targets progenitor cell plasticity as a profibrotic mechanism

Detrimental effects of duplicate reads and low complexity regions on RNA- and ChIP-seq data

Background Adapter trimming and removal of duplicate reads are common practices in next-generation sequencing pipelines. Sequencing reads ambiguously mapped to repetitive and low complexity regions can also be problematic for accurate assessment of the biological signal, yet their impact on sequencing data has not received much attention. We investigate how trimming the adapters, removing duplicates, and filtering out reads overlapping low complexity regions influence the significance of biological signal in RNA- and ChIP-seq experiments. Methods We assessed the effect of data processing steps on the alignment statistics and the functional enrichment analysis results of RNA- and ChIP-seq data. We compared differentially processed RNA-seq data with matching microarray data on the same patient samples to determine whether changes in pre-processing improved correlation between the two. We have developed a simple tool to remove low complexity regions, RepeatSoaker, available at https://github.com/mdozmorov/RepeatSoaker, and tested its effect on the alignment statistics and the results of the enrichment analyses. Results Both adapter trimming and duplicate removal moderately improved the strength of biological signals in RNA-seq and ChIP-seq data. Aggressive filtering of reads overlapping with low complexity regions, as defined by RepeatMasker, further improved the strength of biological signals, and the correlation between RNA-seq and microarray gene expression data. Conclusions Adapter trimming and duplicates removal, coupled with filtering out reads overlapping low complexity regions, is shown to increase the quality and reliability of detecting biological signals in RNA-seq and ChIP-seq data

Dysregulated mesenchymal PDGFR‐β drives kidney fibrosis

Abstract Kidney fibrosis is characterized by expansion and activation of platelet‐derived growth factor receptor‐β (PDGFR‐β)‐positive mesenchymal cells. To study the consequences of PDGFR‐β activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR‐β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch toward myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis, and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation, and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR‐β activation resembled those found in patients. In conclusion, PDGFR‐β activation alone is sufficient to induce progressive renal fibrosis and failure, mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression