Reduced retinoic acid synthesis accelerates prophase I and follicle activation

Abstract

<jats:p>In female mammals, reproductive potential is determined during fetal life by the formation of a non-renewable pool of primordial follicles. Initiation of meiosis is one of the defining features of germ cell differentiation, and is well established to commence in response to retinoic acid. WIN 18,446 inhibits the conversion of retinol to retinoic acid, therefore was used to explore the impact of reduced retinoic acid synthesis on meiotic progression and thus germ cell development and subsequent primordial follicle formation. e13.5 mouse fetal ovaries were cultured in vitro and treated with WIN 18,446 for the first 3 days of a total of up to 12 days. Doses as low as 0.01µM reduced transcript levels of the retinoic acid response genes Stra8 and Rarβ without affecting germ cell number. Higher doses resulted in germ cell loss, rescued with the addition of retinoic acid. WIN 18,446 significantly accelerated the progression of prophase I; this was seen as early as 48 hours post treatment using meiotic chromosome spreads, and was still evident after 12 days of culture using Tra98/Msy2 immunostaining. Furthermore, ovaries treated with WIN 18,446 at e13.5 but not at P0 had a higher proportion of growing follicles compared to vehicle controls, thus showing evidence of increased follicle activation. These data therefore indicate that retinoic acid is not necessary for meiotic progression but may have a role in the regulation of its progression and germ cell survival at that time, and provide evidence for a link between meiotic arrest and follicle growth initiation. </jats:p>

Making a good egg: human oocyte health, aging, and in vitro development

“…These studies suggest nonretinoid extraovarian factors are required for the completion of meiosis 1 in the human fetal ovary ( 48 ), although it is possible that suboptimal aspects of in vitro culture might compromise the production of intraovarian support factors. In addition to its essential role in meiosis, evidence from experiments reducing RA production in the fetal ovary supports that it may also be a survival factor for premeiotic germ cells and contribute to the rate of progression of meiosis ( 56 ).…”