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.
Lenti, E., Farinello, D., Yokoyama, K., Penkov, D., Castagnaro, L., Lavorgna, G., et al. (2016). Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development. THE JOURNAL OF CLINICAL INVESTIGATION, 126(7), 2452-2464.
|Citazione:||Lenti, E., Farinello, D., Yokoyama, K., Penkov, D., Castagnaro, L., Lavorgna, G., et al. (2016). Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development. THE JOURNAL OF CLINICAL INVESTIGATION, 126(7), 2452-2464.|
|Tipo:||Articolo in rivista - Articolo scientifico|
|Carattere della pubblicazione:||Scientifica|
|Presenza di un coautore afferente ad Istituzioni straniere:||Si|
|Titolo:||Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development|
|Autori:||Lenti, E; Farinello, D; Yokoyama, K; Penkov, D; Castagnaro, L; Lavorgna, G; Wuputra, K; Sandell, L; Tjaden, N; Bernassola, F; Caridi, N; De Antoni, A; Wagner, M; Kozinc, K; Niederreither, K; Blasi, F; Pasini, D; Majdic, G; Tonon, G; Trainor, P; Brendolan, A|
FARINELLO, DIEGO (Secondo)
|Data di pubblicazione:||2016|
|Rivista:||THE JOURNAL OF CLINICAL INVESTIGATION|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1172/JCI82956|
|Appare nelle tipologie:||01 - Articolo su rivista|
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