title: 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.forename: Elisa
authors.initials: E
authors.lastname: Lenti
authors.forename: Diego
authors.initials: D
authors.lastname: Farinello
authors.forename: Kazunari K
authors.initials: KK
authors.lastname: Yokoyama
authors.forename: Dmitry
authors.initials: D
authors.lastname: Penkov
authors.forename: Laura
authors.initials: L
authors.lastname: Castagnaro
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lavorgna
authors.forename: Kenly
authors.initials: K
authors.lastname: Wuputra
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Sandell
authors.forename: Naomi E Butler
authors.initials: NE
authors.lastname: Tjaden
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernassola
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Caridi
authors.forename: Anna
authors.initials: A
authors.lastname: De Antoni
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.forename: Katja
authors.initials: K
authors.lastname: Kozinc
authors.forename: Karen
authors.initials: K
authors.lastname: Niederreither
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
authors.forename: Diego
authors.initials: D
authors.lastname: Pasini
authors.forename: Gregor
authors.initials: G
authors.lastname: Majdic
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.forename: Paul A
authors.initials: PA
authors.lastname: Trainor
authors.forename: Andrea
authors.initials: A
authors.lastname: Brendolan
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000502:physiology*; D006720:Homozygote; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D015398:Signal Transduction; D013154:Spleen / Q000254:growth & development*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C487378:Tlx1 protein, mouse; D014212:Tretinoin