ATRA and KL promote differentiation toward the meiotic program of male germ cells.
While it is known that retinoic acid (RA) induces meiosis in mouse female fetal gonads, the mechanisms which regulate this process during spermatogenesis are poorly understood. We show that the All trans RA derivative (ATRA) and Kit Ligand (KL) increase meiotic entry of postnatal mouse spermatogonia in vitro without synergism. Competence to enter meiosis is reached by spermatogonia only at the stage in which they undergo Kit-dependent divisions. Besides increasing Kit expression in spermatogonia, ATRA also upregulates KL expression in Sertoli cells. Both ATRA and KL increase the expression of Stimulated by Retinoic Acid Gene 8 and Dmc1, an early meiotic marker. A specific Kit tyrosine kinase inhibitor prevents the increase in the number of meiotic cells induced by both the two factors, suggesting that they converge on common Kit-dependent signalling pathways. Meiotic entry induced by ATRA and KL is independent from their ability to affect germ cell viability, and is mediated by the activation of PI3K and MAPK pathways through Kit autophosphorylation. ATRA-induced phosphorylation of the two downstream kinases is mediated by a non-genomic mechanism. These data suggest that RA may control the timing of meiosis by influencing both the somatic and the germ cell compartment of the postnatal testis through the activation of the KL/Kit system.
Pellegrini
Manuela
M
Department of Public Health and Cellular Biology, University of Rome 'Tor Vergata', Rome.
Filipponi
Doria
D
Gori
Manuele
M
Barrios
Florencia
F
Lolicato
Francesca
F
Grimaldi
Paola
P
Rossi
Pellegrino
P
Jannini
Emmanuele A
EA
Geremia
Raffaele
R
Dolci
Susanna
S
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D008297:Male; D008540:Meiosis; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D028044:Phosphate-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D013091:Spermatogenesis; D013093:Spermatogonia / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D009687:Nuclear Proteins; D028044:Phosphate-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D019089:Stem Cell Factor; D014212:Tretinoin; C513032:Dmc1 protein, mouse; C102019:Stra8 protein, mouse; C490062:Sycp3 protein, mouse