Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development

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

Research output: Contribution to journalArticle

Abstract

The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome P450 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insights into the molecular determinants of human congenital asplenia.

Original languageEnglish
Pages (from-to)2452-2464
Number of pages13
JournalJournal of Clinical Investigation
Volume126
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

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Tretinoin
Transcription Factors
Spleen
Steroidogenic Factor 1
Organogenesis
Cytochrome P-450 Enzyme System
Genes
Cell Differentiation
Pharmacology
Mutation
Growth
Infection

ASJC Scopus subject areas

  • Medicine(all)

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Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development. / Lenti, E.; Farinello, Diego; Yokoyama, Kazunari K.; Penkov, Dmitri; Castagnaro, Laura; Lavorgna, Giovanni; Wuputra, Kenly; Sandell, Lisa L.; Tjaden, Naomi E Butler; Bernassola, Francesca; Caridi, Nicoletta; De Antoni, Anna; Wagner, Michael; Kozinc, Katja; Niederreither, Karen; Blasi, Francesco; Pasini, Diego; Majdič, Gregor; Tonon, Giovanni; Trainor, Paul A.; Brendolan, Andrea.

In: Journal of Clinical Investigation, Vol. 126, No. 7, 01.07.2016, p. 2452-2464.

Research output: Contribution to journalArticle

Lenti, E, Farinello, D, Yokoyama, KK, Penkov, D, Castagnaro, L, Lavorgna, G, Wuputra, K, Sandell, LL, Tjaden, NEB, Bernassola, F, Caridi, N, De Antoni, A, Wagner, M, Kozinc, K, Niederreither, K, Blasi, F, Pasini, D, Majdič, G, Tonon, G, Trainor, PA & Brendolan, A 2016, 'Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development', Journal of Clinical Investigation, vol. 126, no. 7, pp. 2452-2464. https://doi.org/10.1172/JCI82956
Lenti, E. ; Farinello, Diego ; Yokoyama, Kazunari K. ; Penkov, Dmitri ; Castagnaro, Laura ; Lavorgna, Giovanni ; Wuputra, Kenly ; Sandell, Lisa L. ; Tjaden, Naomi E Butler ; Bernassola, Francesca ; Caridi, Nicoletta ; De Antoni, Anna ; Wagner, Michael ; Kozinc, Katja ; Niederreither, Karen ; Blasi, Francesco ; Pasini, Diego ; Majdič, Gregor ; Tonon, Giovanni ; Trainor, Paul A. ; Brendolan, Andrea. / Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 7. pp. 2452-2464.
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