Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development
Elisa Lenti, … , Paul A. Trainor, Andrea Brendolan
Elisa Lenti, … , Paul A. Trainor, Andrea Brendolan
Published May 23, 2016
Citation Information: J Clin Invest. 2016;126(7):2452-2464. https://doi.org/10.1172/JCI82956.
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Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development

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.

Authors

Elisa Lenti, Diego Farinello, Kazunari K. Yokoyama, Dmitry 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 Majdic, Giovanni Tonon, Paul A. Trainor, Andrea Brendolan

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Figure 1

TLX1 controls RA signaling pathway.

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TLX1 controls RA signaling pathway. (A) GSEA enrichment plots and heat m...
(A) GSEA enrichment plots and heat maps of differentially expressed genes belonging to the RA pathway associated with loss of Tlx1. The bar-code plot indicates the position of the genes on the expression data rank-sorted by its association with Tlx1 mutants, with red and blue colors indicating over- and underexpression in the mRNA. Validation of RA-associated genes by qPCR was performed on Tlx1+/– and Tlx1–/– embryonic spleens. The means of triplicates ± SD are shown, *P < 0.05, **P < 0.01 (2-tailed Student’s t test). Data are representative of 1 of 2 different validation experiments with 8–10 pooled spleens for each genotype. (B) TLX1 peak annotation relative to the indicated genomic feature. TLX1 ChIP-seq was performed in the eSMC line, and peak call was generated by comparison with an unrelated ChIP-seq experiment using rabbit IgG as control. MEME motif prediction of DNA sequences enriched in TLX1 ChIP-seq. ChIP-qPCR analysis of TLX1 binding in eSMC line. Positive (R1, R3, and R5) and negative (R2, R4, and R6) binding regions are indicated relative to transcription start site (TSS). Data are normalized to amplification of the input chromatin. Data are representative of 1 of 3 independent experiments.