Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development

Lenti, Elisa; Farinello, Diego; Yokoyama, Kazunari K.; Penkov, Dmitry; Castagnaro, Laura; Lavorgna, G; Wuputra, Kenly; Sandell, Lisa L.; Tjaden, Naomi E. Butler; Bernassola, Francesca; Caridi, Nicoletta; A, De Antoni; Wagner, Michael; Kozinc, Katja; Niederreither, Karen; Blasi, Francesco; Pasini, Diego; Majdič, Gregor; Tonon, Giovanni; Trainor, Paul A.; Brendolan, Andrea

doi:10.1172/jci82956

Cited by 32 publications

(19 citation statements)

References 80 publications

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“…Both Cyp26b1 -/and Cyp26b1 Δ 10/Δ10 embryos exhibited many of the same developmental defects previously described, including limb defects, craniofacial abnormalities, micrognathia, cleft palate, skin abnormalities, and spleen hypoplasia, although edema and hemorrhages were not observed at this stage as previously described ( Fig. 2A-B) (Bowles et al, 2014;Dranse et al, 2011;Lenti et al, 2016;Okano et al, 2012a;Okano et al, 2012b;Yashiro et al, 2004). Additionally, Cyp26b1 -/mice died shortly after birth and exhibited signs of respiratory distress, including air hunger mirroring the previously generated null model.…”

Section: Generation Of Cyp26b1 Null Mice Using Crispr/cas9supporting

confidence: 80%

Cyp26b1 is required for proper airway epithelial differentiation during lung development

Daniel

Sutton

Htike

et al. 2019

Preprint

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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

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Section: Generation Of Cyp26b1 Null Mice Using Crispr/cas9supporting

confidence: 80%

Cyp26b1 is required for proper airway epithelial differentiation during lung development

Daniel

Sutton

Htike

et al. 2019

Preprint

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“…The previous observations suggested that RDH10-mediated retinol metabolism is important for early gland development, but the overall dysmorphology of rare surviving E12.5 Rdh10 −/− mutant embryos makes such phenotypes difficult to interpret. To better assess the role of RDH10 at initiation stages of SMG development, we utilized a tamoxifen-inducible Rdh10 knockout model (Kurosaka et al, 2017;Lenti et al, 2016;Sandell et al, 2012), which enables stage-specific inactivation of Rdh10. The genetic cross used for inactivation of Rdh10 involved a combination of Rdh10 mutant alleles (Fig.…”

Section: Stage-specific Inactivation Of Rdh10 Attenuates Ra Signalingmentioning

confidence: 99%

RDH10-mediated retinol metabolism and RARα-mediated retinoic acid signaling are required for submandibular salivary gland initiation

et al. 2018

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In mammals, the epithelial tissues of major salivary glands generate saliva and drain it into the oral cavity. For submandibular salivary glands (SMGs), the epithelial tissues arise during embryogenesis from naïve oral ectoderm adjacent to the base of the tongue, which begins to thicken, express SOX9 and invaginate into underlying mesenchyme. The developmental mechanisms initiating salivary gland development remain unexplored. In this study, we show that retinoic acid (RA) signaling activity at the site of gland initiation is colocalized with expression of retinol metabolic genes Rdh10 and Aldh1a2 in the underlying SMG mesenchyme. Utilizing a novel ex vivo assay for SMG initiation developed for this study, we show that RDH10 and RA are required for salivary gland initiation. Moreover, we show that the requirement for RA in gland initiation involves canonical signaling through retinoic acid receptors (RAR). Finally, we show that RA signaling essential for gland initiation is transduced specifically through RARα, with no contribution from other RAR isoforms. This is the first study to identify a molecular signal regulating mammalian salivary gland initiation.

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“…TLX1 is a transcription factor that controls the cell fate specification and organ expansion during spleen development. 33 Tlx1 deletion in mice causes asplenia. 34 Moreover, many studies have showed that TLX1 was associated with T-cell acute lymphoblastic leukemia.…”

Section: Discussionmentioning

confidence: 99%

<p>Long Non-Coding RNA BCAR4 Binds to miR-644a and Targets TLX1 to Promote the Progression of Bladder Cancer</p>

Wang

et al. 2020

OTT

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Background: Bladder cancer is a serious threat to human health. It is meaningful to study the pathogenesis of bladder cancer. Long non-coding RNAs (lncRNAs) are reported to promote or inhibit bladder cancer development. However, the role of lncRNA BCAR4 in the regulation of bladder cancer remains unclear. Purpose: This study was to explore the role of lncRNA BCAR4 in the progression of bladder cancer cell. Methods: RT-PCR was used to examine the expression of BCAR4 and miR-644a. CCK8 assay, colony formation assay, Transwell assay were used to detect the progression of bladder cancer cells after transfecting of indicated plasmids. Results: The expression of BCAR4 was higher in bladder cancer cell lines than normal urothelial cell line. Moreover, the expression of BCAR4 was associated with the advanced stage and metastasis of bladder cancer. Through knockdown of BCAR4, we discovered that knockdown of BCAR4 significantly decreased the proliferation, migration and invasive abilities of bladder cancer cells. Mechanically, we showed that BCAR4 can bind to miR-644a directly and targets TLX1. Moreover, we also showed that miR-644a was also highly expressed in bladder cancer cells and inhibition of miR-644a or overexpression of TLX1 can increased the migration abilities of bladder cancer caused by knockdown of BCAR4. Conclusion: We showed that BCAR4 sponged miR-644a to modulate the expression of TLX1 and promote bladder cancer development.

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Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development

Cited by 32 publications

References 80 publications

Cyp26b1 is required for proper airway epithelial differentiation during lung development

Cyp26b1 is required for proper airway epithelial differentiation during lung development

RDH10-mediated retinol metabolism and RARα-mediated retinoic acid signaling are required for submandibular salivary gland initiation

<p>Long Non-Coding RNA BCAR4 Binds to miR-644a and Targets TLX1 to Promote the Progression of Bladder Cancer</p>

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