Platelet-derived growth factor receptor alpha regulates fetal testis differentiation via an ERK–CREB axis

<i>Platelet-derived growth factor receptor alpha</i> (<i>Pdgfra</i>) plays a crucial role in mesenchymal cell differentiation, but the molecular signaling involved in this process remains unclear, particularly within the fetal testis. Here, we use XY <i>Pdgfra</i>-null gonads to investigate the molecular mechanisms underlying testicular organogenesis, focusing on the formation of testicular architecture and the differentiation of fetal Leydig cells (FLCs), the steroidogenic lineage arising from mesenchymal precursors within the testicular interstitial compartment. The extracellular signal-regulated kinase (ERK) pathway, a well-known mitogen-activated signaling pathway, was significantly inhibited in XY <i>Pdgfra</i>-null gonads, suggesting that ERK signaling is activated downstream of PDGFRA. Using ex vivo whole-organ culture, small interfering RNA cell culture methods, transwell assays, and a genetic mouse model to disrupt ERK signaling in gonadal cells, we found that the ERK pathway promotes testis cord formation via <i>early growth response 1</i>-mediated cell migration and regulates the expression of steroidogenic enzymes in FLCs via activating the transcription factor cAMP responsive element binding protein 1. These findings highlight the significance of the PDGFRA signaling network in fetal testis organogenesis, thus providing insights into mesenchymal cell differentiation and the etiology of congenital disorders related to gonadal development.