PDGF‐AA activates AKT and ERK signaling for testicular interstitial Leydig cell growth via primary cilia

Abstract

Testes control the development of male reproductive system. The testicular interstitial Leydig cells (Leydig cells) synthesize testosterone for promoting spermatogenesis and secondary sexual characteristics. Type A platelet-derived growth factor (PDGF-AA) is one of the most important growth factors in regulating Leydig cell growth and function. Knockout of PDGF-AA or its congenital receptor PDGFR-α leads to poor testicular development caused by reducing Leydig cell numbers, supporting PDGF-AA/PDGFR-α signaling regulates Leydig cell development. Primary cilium is a cellular antenna that functions as an integrative platform to transduce extracellular signaling for proper development and differentiation. Several receptors including PDGFR-α are observed on primary cilia for initiating signaling cascades in distinct cell types. Here we showed that PDGF-AA/PDGFR-α signaling promoted Leydig cells growth, migration, and invasion via primary cilia. Upon PDGF-AA treatment, AKT and ERK signaling were activated to regulate these cellular events. Interestingly, active AKT and ERK were detected around the base of primary cilia. Depletion of ciliary genes (IFT88 and CEP164) alleviated PDGF-AA-activated AKT and ERK, thus reducing Leydig cell growth, migration, and invasion. Thus, our study not only reveals the function of PDGF-AA/PDGFR-α signaling in maintaining testicular physiology but also uncovers the role of primary cilium and downstream signaling in regulating Leydig cell development.

Testis morphogenesis and fetal Leydig cell development are mediated through ERK signaling activated by platelet derived growth factor receptor alpha

“…The MEK/ERK cascade in LCs is critical for maintenance of a functional population of ALCs in the adult testis, as deletion of Mek1 and Mek2 (official names Map2k1 and Map2k2) in Cyp17a1-positive LCs resulted in a decreased number of CYP11A1-positive ALCs 18 . Furthermore, in the adult testis, PDGF-AA is able to activate ERK signaling in ALCs in vitro 47 , suggesting that PDGFA is the critical ligand. In Pdgfra-null XY gonads, the activation of ERK was reduced in endothelial, interstitial, and Sertoli cells.…”

MicroRNA‑155‑5p inhibits trophoblast cell proliferation and invasion by disrupting centrosomal function

“…Primary cilia are observed in the placenta during the first trimester of pregnancy. These primary cilia activate extracellular signal-regulated kinase (ERK) signaling to promote placenta formation (29,30). Thus, defective primary cilia formation leads to preeclampsia and other complications such as gestational diabetes mellitus (30).…”