Retinoic Acid Receptor-Dependent, Cell-Autonomous, Endogenous Retinoic Acid Signaling and Its Target Genes in Mouse Collecting Duct Cells

Wong, Yuen Fei; Wilson, Patricia D.; Unwin, Robert J.; Norman, Jill T.; Arno, Matthew; Hendry, Bruce M.; Xu, Qihe

doi:10.1371/journal.pone.0045725

Cited by 16 publications

(19 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also for Sprr1a, Prss35,and Rnf183 the number of studies is limited. Sprr1a has been shown to be regulated by the all‐trans retinoic acid pathway in mIMCD3 cells (38) but no studies describing the physiologic function of these genes in the kidney are available. This study opens the opportunity for further analysis of these genes, to explore their role on renal function.…”

Section: Discussionmentioning

confidence: 99%

The kidney‐specific expression of genes can be modulated by the extracellular osmolality

et al. 2016

View full text Add to dashboard Cite

With this study, we wanted to prove the hypothesis that the unique extracellular osmolality within the renal medulla modulates a specific gene expression pattern. The physiologic functions of the kidneys are mediated by the segment-specific expression of key proteins. So far, we have limited knowledge about the mechanisms that control this gene expression pattern. The hyperosmolality in the renal medullary interstitium is of major importance as a driving force for urine concentration. We made use of primarily cultured rat renal inner medullary collecting-duct cells and microarray analysis to identify genes affected by the environmental osmolality of the culture medium. We identified hundreds of genes that were either induced or repressed in expression by hyperosmolality in a time- and osmolality-dependent fashion. Further analysis demonstrated that many of them, physiologically, showed a kidney- and even collecting-duct-specific expression, including secreted proteins, kinases, and transcription factors. On the other hand, we identified factors, down-regulated in expression, that have a diuretic effect. In conclusion, the kidney is the only organ that has such a hyperosmotic environment, and study provides an excellent method for controlling tissue-specific gene expression.-Schulze Blasum, B., Schröter, R., Neugebauer, U., Hofschröer, V., Pavenstädt, H., Ciarimboli, G., Schlatter E., Edemir, B. The kidney-specific expression of genes can be modulated by the extracellular osmolality.

show abstract

Section: Discussionmentioning

confidence: 99%

The kidney‐specific expression of genes can be modulated by the extracellular osmolality

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Here we show that, indeed, the synthetic enzymes, Rdh10, Raldh1, 2, and 3, are down‐regulated while the catabolic enzyme Cyp26a1 is up‐regulated in the presence of high endogenous levels of ATRA in Dhrs3 –/– embryos. ATRA also up‐regulates the expression of Dhrs3 itself (21, 22, 24–27), which limits the amount of ATRA by increasing the rate of reduction of all‐ trans ‐retinaldehyde to all‐ trans‐retinol. In summary, these results demonstrate that DHRS3 carries out an essential and evolutionarily conserved role in the feedback regulation of ATRA formation.…”

Section: Discussionmentioning

confidence: 99%

The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development

Billings¹,

Pierzchalski²,

et al. 2013

View full text Add to dashboard Cite

Oxidation of retinol via retinaldehyde results in the formation of the essential morphogen all-trans-retinoic acid (ATRA). Previous studies have identified critical roles in the regulation of embryonic ATRA levels for retinol, retinaldehyde, and ATRA-oxidizing enzymes; however, the contribution of retinaldehyde reductases to ATRA metabolism is not completely understood. Herein, we investigate the role of the retinaldehyde reductase Dhrs3 in embryonic retinoid metabolism using a Dhrs3-deficient mouse. Lack of DHRS3 leads to a 40% increase in the levels of ATRA and a 60% and 55% decrease in the levels of retinol and retinyl esters, respectively, in Dhrs3(-/-) embryos compared to wild-type littermates. Furthermore, accumulation of excess ATRA is accompanied by a compensatory 30-50% reduction in the expression of ATRA synthetic genes and a 120% increase in the expression of the ATRA catabolic enzyme Cyp26a1 in Dhrs3(-/-) embryos vs. controls. Excess ATRA also leads to alterations (40-80%) in the expression of several developmentally important ATRA target genes. Consequently, Dhrs3(-/-) embryos die late in gestation and display defects in cardiac outflow tract formation, atrial and ventricular septation, skeletal development, and palatogenesis. These data demonstrate that the reduction of retinaldehyde by DHRS3 is critical for preventing formation of excess ATRA during embryonic development.

show abstract

“…Although they did not test the effect of removing RA individually, this study is consistent with the model that RA inhibits differentiation of the distal airways. Similarly, hyperactive RA signaling through constitutively active RARα or RARβ lead to defects in distal airway formation (Wongtrakool et al, 2003). Interestingly, lungs with the constitutively active RARα transgene had a complete loss of AT2 and AT1 cells whereas lungs with the constitutively active RARβ transgene did contain some AT2 and AT1 cells, more closely mirroring Cyp26b1 -/lungs.…”

Section: Discussionmentioning

confidence: 99%

“…We next asked whether other targets of RA signaling are altered in Cyp26b1 -/lungs. We first analyzed expression levels of Ret, Egr1, Foxa1, and Pbx1, which have all been shown to be direct targets of RA signaling in other contexts (Balmer and Blomhoff, 2002;Probst et al, 2011;Rhinn and Dolle, 2012;Wong et al, 2012). qRT-PCR analyses of whole lung lysates for these genes revealed significant upregulation of Ret but not the other 3 genes (Fig.…”

Section: Cyp26b1 Mutant Lungs Exhibit a Partial Ra Responsementioning

confidence: 99%

“…Culturing E12.5 lung explants with RA led to a reduction in branching due to decreased Fgf10 (Malpel et al, 2000). Likewise, forcing increased RA signaling in distal lung epithelial cells through a constitutively active RAR in vivo prevents distal saccule differentiation (Wongtrakool et al, 2003). Lastly, a third, separate role for RA occurs postnatally during alveolar maturation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cyp26b1 is required for proper airway epithelial differentiation during lung development

Daniel

Sutton

Htike

et al. 2019

Preprint

View full text Add to dashboard Cite

Proper organ development depends on coordinated communication between multiple cell types. Retinoic acid (RA) is an autocrine and paracrine signaling molecule critical for the development of most organs including the lung. Both RA excess and deficiency lead to drastic alterations in embryogenesis, often culminating in embryonic or neonatal lethality. Therefore, RA levels must be spatially and temporally titrated to ensure proper organogenesis. Despite extensive work detailing the effects of RA deficiency in early lung morphogenesis, little is known about how RA levels are modulated during late lung development. Here, we investigate the role of the RA catabolizing protein Cyp26b1 in lung development. Cyp26b1 is highly enriched in lung endothelial cells (ECs) throughout the course of development. We find that loss of Cyp26b1 impacts differentiation of the distal epithelium without appreciably affecting proximal airways, EC lineages, or stromal populations. Cyp26b1−/− lungs exhibit an increase in cellular density, with an expansion of distal progenitors at the expense of alveolar type 1 (AT1) cells, which culminates in neonatal death. Exogenous administration of RA in late gestation was able to partially reproduce this defect in epithelial differentiation; however, transcriptional analyses of Cyp26b1−/− lungs and RA-treated lungs reveal separate, but overlapping, transcriptional responses. These data suggest that the defects observed in Cyp26b1−/− lungs are caused by both RA-dependent and RA-independent mechanisms. This work highlights critical cellular crosstalk during lung development involving a crucial role for Cyp26b1-expressing endothelium, and identifies a novel RA rheostat in lung development.HIGHLIGHTSCyp26b1 is highly expressed in lung ECs throughout developmentCyp26b1-null lungs fail to undergo proper differentiation of distal epithelium leading to an increase in progenitors and AT2 cells at the expense of AT1 cellsFunctional and transcriptional analyses suggest both RA-dependent and RA-independent mechanisms

show abstract

Retinoic Acid Receptor-Dependent, Cell-Autonomous, Endogenous Retinoic Acid Signaling and Its Target Genes in Mouse Collecting Duct Cells

Cited by 16 publications

References 51 publications

The kidney‐specific expression of genes can be modulated by the extracellular osmolality

The kidney‐specific expression of genes can be modulated by the extracellular osmolality

The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development

Cyp26b1 is required for proper airway epithelial differentiation during lung development

Contact Info

Product

Resources

About