Brg1 Determines Urothelial Cell Fate during Ureter Development

Weiß, Robert M.; Guo, Sheng; Shan, Alan; Shi, Hongmei; Romano, Rose‐Anne; Sinha, Satrajit; Cantley, Lloyd G.; Guo, Jian‐Kan

doi:10.1681/asn.2012090902

Cited by 22 publications

(13 citation statements)

References 31 publications

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“…Also, mutations in certain genes induce hydronephrosis in animals and humans (41-43). It is interesting that orally administered SCFAs can also induce UPJ obstruction.…”

Section: Discussionmentioning

confidence: 99%

Chronically Elevated Levels of Short-Chain Fatty Acids Induce T Cell–Mediated Ureteritis and Hydronephrosis

Park

Goergen

HogenEsch

et al. 2016

The Journal of Immunology

146

104

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Short-chain fatty acids (SCFAs) are major products of gut microbial fermentation and profoundly affect host health and disease. SCFAs generate IL-10+ regulatory T cells, which may promote immune tolerance. However, SCFAs can also induce Th1 and Th17 cells upon immunological challenges and, therefore, also have the potential to induce inflammatory responses. Because of the seemingly paradoxical SCFA activities in regulating T cells, we investigated, in depth, the impact of elevated SCFA levels on T cells and tissue inflammation in mice. Orally administered SCFAs induced effector (Th1 and Th17) and regulatory T cells in ureter and kidney tissues, and they induced T cell–mediated ureteritis, leading to kidney hydronephrosis (hereafter called acetate-induced renal disease, or C2RD). Kidney hydronephrosis in C2RD was caused by ureteral obstruction, which was, in turn, induced by SCFA-induced inflammation in the ureteropelvic junction and proximal ureter. Oral administration of all major SCFAs, such as acetate, propionate, and butyrate, induced the disease. We found that C2RD development is dependent on mammalian target of rapamycin activation, T cell–derived inflammatory cytokines such as IFN-γ and IL-17, and gut microbiota. Young or male animals were more susceptible than old or female animals, respectively. However, SCFA receptor (GPR41 or GPR43) deficiency did not affect C2RD development. Thus, SCFAs, when systemically administered at levels higher than physiological levels, cause dysregulated T cell responses and tissue inflammation in the renal system. The results provide insights into the immunological and pathological effects of chronically elevated SCFAs.

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“…Also, mutations in certain genes induce hydronephrosis in animals and humans (41-43). It is interesting that orally administered SCFAs can also induce UPJ obstruction.…”

Section: Discussionmentioning

confidence: 99%

Chronically Elevated Levels of Short-Chain Fatty Acids Induce T Cell–Mediated Ureteritis and Hydronephrosis

Park

Goergen

HogenEsch

et al. 2016

The Journal of Immunology

146

104

View full text Add to dashboard Cite

show abstract

“…Around birth, the three epithelial and mesenchymal cell layers can be histologically clearly distinguished. 3,4 Embryologic experiments have shown that the survival, patterning, and subsequent differentiation of the primitive ureteric epithelium and its surrounding mesenchyme depend on each other. Genetic analysis has identified some of the trans-acting signals and the downstream transcription factors that regulate these cellular programs.…”

mentioning

confidence: 99%

Diversification of Cell Lineages in Ureter Development

Bohnenpoll

Feraric

Nattkemper

et al. 2016

JASN

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The mammalian ureter consists of a mesenchymal wall composed of smooth muscle cells and surrounding fibrocytes of the tunica adventitia and the lamina propria and an inner epithelial lining composed of layers of basal, intermediate, and superficial cells. How these cell types arise from multipotent progenitors is poorly understood. Here, we performed marker analysis, cell proliferation assays, and genetic lineage tracing to define the lineage relations and restrictions of the mesenchymal and epithelial cell types in the developing and mature mouse ureter. At embryonic day (E) 12.5, the mesenchymal precursor pool began to subdivide into an inner and outer compartment that began to express markers of smooth muscle precursors and adventitial fibrocytes, respectively, by E13.5. Smooth muscle precursors further diversified into lamina propria cells directly adjacent to the ureteric epithelium and differentiated smooth muscle cells from E16.5 onwards. Uncommitted epithelial progenitors of the ureter differentiated into intermediate cells at E14.5. After stratification into two layers at E15.5 and three cell layers at E18.5, intermediate cells differentiated into basal cells and superficial cells. In homeostasis, proliferation of all epithelial and mesenchymal cell types remained low but intermediate cells still gave rise to basal cells, whereas basal cells divided only into basal cells. These studies provide a framework to further determine the molecular mechanisms of cell differentiation in the tissues of the developing ureter.

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“…Brg1-null mice die during the peri-implantation stage, whereas Brm-null mice develop normally (Bultman et al, 2000;Reyes et al, 1998). Recent studies showed that Brg1 is essential for development or homeostasis of various organs and cell types, including heart (Hang et al, 2010;Takeuchi et al, 2011), vasculature (Davis et al, 2013;Griffin et al, 2008Griffin et al, , 2011, ureter (Weiss et al, 2013), smooth muscle (Zhang et al, 2011) and neurons (Li et al, 2013;Matsumoto et al, 2006;Seo et al, 2005). In the intestine, Brg1 is essential for maintenance of intestinal stem cells (Holik et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

97 BRG1 Plays an Essential Role in Development and Homeostasis of the Duodenum Through Regulation of Notch Signaling

Takada¹,

Fukuda²,

Chiba³

et al. 2016

Gastroenterology

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Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for development and homeostasis of various organs. However, the functional role of Brg1 in intestinal development and homeostasis, and the underlying molecular mechanism, remain unknown. We found that deletion of Brg1 in the mouse intestine resulted in growth impairment and early death associated with abnormal crypt-villous formation, skewed differentiation into secretory lineage cells, markedly increased apoptosis, and stem cell loss in the duodenum. Furthermore, we found that the Notch signaling pathway was dramatically downregulated in Brg1-deficient duodenum. Remarkably, overexpression of the Notch1 intercellular domain (ICD) partially reversed the prognosis of intestinal Brg1 mutant mice. Notch1 ICD overexpression rescued morphogenesis, prevented over-differentiation into secretory lineage cells, and restored apoptosis to normal levels in Brg1-deficient duodenum, although stem cell loss was not rescued. Our data demonstrate that Brg1 plays an essential role in development and homeostasis, including morphogenesis, stem cell differentiation and cell survival in the duodenum. Mechanistically, the rescue of the intestinal Brg1 mutant phenotype by overexpression of the Notch1 ICD indicates that Notch signaling is a key downstream target that mediates the effects of Brg1.

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Brg1 Determines Urothelial Cell Fate during Ureter Development

Cited by 22 publications

References 31 publications

Chronically Elevated Levels of Short-Chain Fatty Acids Induce T Cell–Mediated Ureteritis and Hydronephrosis

Chronically Elevated Levels of Short-Chain Fatty Acids Induce T Cell–Mediated Ureteritis and Hydronephrosis

Diversification of Cell Lineages in Ureter Development

97 BRG1 Plays an Essential Role in Development and Homeostasis of the Duodenum Through Regulation of Notch Signaling

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