Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development [Microarray Expression]

The molecular mechanisms underlying asplenia, a condition often associated with overwhelming infections remain largely unknown. During spleen development, the transcription factor TLX1 controls morphogenesis and organ expansion, and loss of it causes spleen agenesis. However, the downstream signaling pathways that are deregulated in the absence of TLX1 are mostly unknown. Herein, we demonstrate that loss of Tlx1 in the splenic mesenchyme causes increased retinoic acid (RA) signaling. Increased RA activity causes premature differentiation of the splenic mesenchyme and reduced vasculogenesis of the splenic anlage. Moreover, excess or deficiency in RA signaling, as observed in Cyp26b1 or Rdh10 mutants respectively, also results in spleen growth arrest. Genome-wide analysis revealed that TLX1 binds RA-associated genes through the AP-1 site and cooperates with the AP-1 family transcription factors to regulate transcription. Pharmacological inhibition of RA signaling partially rescues the spleen defect. These findings establish the critical role of TLX1 in controlling RA metabolism, and provide novel mechanistic insights into the molecular determinants underlying congenital asplenia.

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Lenti E, Farinello D, Yokoyama KK, Penkov D, Castagnaro L, Lavorgna G, Wuputra K, Sandell LL, Tjaden NE, Bernassola F, Caridi N, De Antoni A, Wagner M, Kozinc K, Niederreither K, Blasi F, Pasini D, Majdic G, Tonon G, Trainor PA, Brendolan A