Biology subjects

Potter, A. S.

Publications and source records attributed to Potter, A. S..

3 recordsLinked to original sources

bioRxiv2022

Interstitial Notch signaling regulates nephron development via the Gata3-Renin axis in the mouse kidney

Notch signaling in the renal interstitium is known to be required for the formation of mesangial cells and Ren1 (Renin)-expressing cells. However, little is known about how interstitial Notch signaling affects nephron development. We found that blocking Notch signaling in the renal interstitium in mice caused developmental arrest of proximal tubules accompanied by defective formation of mesangial cells. We examined the interstitial Pdgfrb mutant kidney which exhibits a similar mesangial cell defect and found that the Pdgfrb mutant kidney showed normal proximal tubule development, suggesting that the absence of mesangial cells was not the cause of defective proximal tubule development. Our single cell RNA-seq analysis of the interstitial Rbpj mutant kidney showed that a subset of proximal tubule genes were downregulated in the mutant kidney and that Gata3 was downregulated in the mutant interstitium during the development of Ren1-expressing cells. We found that deleting Gata3 in the interstitium caused the loss of Renin and the developmental arrest of proximal tubules, phenocopying the interstitial Notch/Rbpj mutants. Our results suggest that interstitial Notch signaling regulates the development of proximal tubules via the Gata3-Renin axis in the mouse kidney.

developmental biology↗

bioRxiv2019

A Bigenic mouse model of FSGS reveals perturbed pathways in podocytes, mesangial cells and endothelial cells

Focal segmental glomerulosclerosis is a major cause of end stage renal disease. Many patients prove unresponsive to available therapies. An improved understanding of the molecular basis of the disease process could provide insights leading to novel therapeutic approaches. In this study we carried out an RNA-seq analysis of the altered gene expression patterns of podocytes, mesangial cells and glomerular endothelial cells of the bigenic Cd2ap+/-, Fyn-/- mutant mouse model of FSGS. In the podocytes we observed upregulation of many genes related to the Tgf{beta} family/pathway, including Gdnf, Tgf{beta}1, Tgf{beta}2, Snai2, Vegfb, Bmp4, and Tnc. The mutant podocytes also showed upregulation of Acta2, a marker of smooth muscle and associated with myofibroblasts, which are implicated in driving fibrosis. GO analysis of the podocyte upregulated genes identified elevated protein kinase activity, increased expression of growth factors, and negative regulation of cell adhesion, perhaps related to the observed podocyte loss. Both podocytes and mesangial cells showed strong upregulation of aldehyde dehydrogenase genes involved in the synthesis of retinoic acid. Similarly, the Cd2ap+/-, Fyn-/- mesangial cells, as well as podocytes in other genetic models, and the glomeruli of human FSGS patients, all show upregulation of the serine protease Prss23, with the common thread suggesting important functionality. Another gene with strong upregulation in the Cd2ap+/-, Fyn-/- mutant mesangial cells as well as multiple other mutant mouse models of FSGS was thrombospondin, which activates the secreted inactive form of Tgf{beta}. The Cd2ap+/-, Fyn-/- mutant endothelial cells showed elevated expression of genes involved in cell proliferation, angioblast migration, angiogenesis, and neovasculature, all consistent with the formation of new blood vessels in the diseased glomerulus. The resulting global definition of the perturbed molecular pathways in the three major cell types of the mutant glomerulus provide deeper understanding of the molecular pathogenic pathways.

pathology↗

bioRxiv2018

Single cell RNA-seq study of wild type and Hox9,10,11 mutant developing uterus

The uterus is a remarkable organ that must guard against infections while maintaining the ability to support growth of a fetus without rejection. The Hoxa10 and Hoxa11 genes have previously been shown to play essential roles in uterus development and function. In this report we show that the Hoxc9,10,11 genes play a redundant role in the formation of uterine glands. In addition, we use single cell RNA-seq to create a high resolution gene expression atlas of the developing wild type mouse uterus. Cell types and subtypes are defined, for example dividing endothelial cells into arterial, venous, capillary, and lymphatic, while epithelial cells separate into luminal and glandular subtypes. Further, a surprising heterogeneity of stromal and myocyte cell types are identified. Transcription factor codes and ligand/receptor interactions are characterized. We also used single cell RNA-seq to globally define the altered gene expression patterns in all developing uterus cell types for two Hox mutants, with 8 or 9 mutant Hox genes. The mutants show a striking disruption of Wnt signaling as well as the Cxcl12/Cxcr4 ligand/receptor axis.\n\nSummary statementA single cell RNA-seq study of the developing mouse uterus defines cellular heterogeneities, lineage specific gene expression programs and perturbed pathways in Hox9,10,11 mutants.

developmental biology↗