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Peptidyl arginine deiminases (PADIs) are enzymes that change the charge of proteins through citrullination. We recently found  Padi2  was expressed exclusively in fetal Sertoli cells. In this study, we analyzed the transcriptional regulation of  Padi2  and the role of PADI2 in testicular development. We showed SOX9 positively regulated  Padi2  transcription and FOXL2 antagonized it in TM3 cells, a model of Sertoli cells. The responsive region to SOX9 and FOXL2 was identified within the  Padi2  sequence by reporter assay. In fetal testes from  Sox9  knockout (AMH-Cre: Sox9   flox/flox  ) mice,  Padi2  expression was greatly reduced, indicating SOX9 regulates  Padi2 in vivo .  In vitro  analysis using siRNA suggested PADI2 modified transcriptional regulation by SOX9. However,  Padi2  −/−  XY mice were fertile and showed no apparent reproductive anomalies. Although, PADI2 is known as an epigenetic transcriptional regulator through H3 citrullination, no significant difference in H3 citrullination between wildtype and  Padi2  −/−  XY gonads was observed. These results suggest  Padi2  is a novel gene involved in testis development that is specifically expressed in Sertoli cells through the regulation by SOX9 and FOXL2 and PADI2 supports regulation of target genes by SOX9. Analysis of the  Padi2  −/−  XY phenotype suggested a redundant factor compensated for PADI2 function in testicular development.

Peptidyl arginine deiminase 2 (Padi2) is expressed in Sertoli cells in a specific manner and regulated by SOX9 during testicular development