In today’s world, the rising concerns over accelerated reproductive aging in women highlights the need to better understand the factors that impact fertility. While much of the research focus is on the oocyte itself, it is now known that the surrounding tissues and general nutrition also play a key role in maintaining oocyte health. One important pathway that regulates reproductive fidelity is the conserved insulin signaling (IS) pathway. This pathway helps an animal sense nutrient and stress levels, and controls energy use. Its optimal functioning through diet management and genetics is associated with longevity. On the other hand, its deregulation (desensitisation or overactivation) is associated with metabolic disorders like diabetes. Additionally, when this pathway malfunctions, fertility issues often arise in research animals as well as in humans.
How insulin signaling pathway impacts fertility?
In Caenorhabditis elegans, a tiny worm widely used for research on development and aging, an optimally functioning and sensitized IS dramatically increases life span and improves oocyte quality, although the reasons are less known. For example, it is not known how different somatic reproductive tissues, like the ovary or the uterus, sense nutrients, developmental abnormalities or stress to influence germ cell development and oocyte quality using the IS. Arnab Mukhopadhyay’s lab at the National Institute of Immunology (NII), led by PhD students Umanshi Rautela is trying to understand this aspect and has recently made an exciting discovery that is now published in PLoS Genetics.
A team of two proteins ensure oocyte quality and reproductive fidelity
Cyclin D is a key regulator of cell division and plays a pivotal role in the formation of healthy oocytes in the germline through a process known as oogenesis. The NII team surprisingly finds an unconventional role of this protein in the uterus, a tissue not directly involved in oocyte production and only harbours the fertilised oocytes. In this paper, they report that in the wild-type worms with more than optimal IS, lowering the level of Cyclin D specifically in the uterus leads to poor oocyte quality. However, in worms with a sensitized and optimally functioning IS, lowering uterine Cyclin D levels halts oocyte production in the germline through a FOXO transcription factor (TF) that regulates important genes controlled by the IS pathway. Strikingly, if the FOXO is also removed in this scenario, oogenesis resumes—but the oocytes produced are of poor quality.
Supported by their findings, researchers propose that the FOXO TF monitors the uterine health as a part of a "surveillance" mechanism. Upon sensing any danger to the uterine tissues (such as lowering of Cyclin D levels) of animals with sensitized IS, the activated FOXO steps in and orchestrates the deterioration of specific reproductive tissues. When these tissues are damaged, oogenesis is arrested. This may at first appear in striking contrast to the grand pro-longevity and pro-tissue maintenance role of FOXO TFs, but by preventing production of suboptimal quality oocytes, FOXO preserves germline integrity and ensures progeny fitness.
This work builds on the team’s earlier publication, led by PhD student Gautam C. Sarkar, in Development in 2023 where they showed that inducing DNA damage specifically in the uterus of worms with sensitized IS also triggered a similar FOXO-dependent arrest of oogenesis. Collectively, these two studies from NII, led by graduate students, highlight the pivotal function of FOXO TF as a protective regulator that halts reproduction when the uterine environment is deemed compromised, ensuring oocyte quality for successful perpetuation of the species. Since the IS pathway is conserved in function in higher mammals, it will be intriguing to determine if similar mechanisms exist in mammals to ensure oocyte quality and reproductive fidelity.
References:
1. Sarkar, G.C., Rautela, U., Goyala, A., Datta, S., Anand, N., Singh, A., Singh, P., Chamoli, M. and Mukhopadhyay, A., 2023. DNA damage signals from somatic uterine tissue arrest oogenesis through activated DAF-16. Development, 150(17), p.dev201472.
2. Rautela, U., Sarkar, G.C., Chaudhary, A., Chatterjee, D., Rosh, M., Arimbasseri, A.G. and Mukhopadhyay, A., 2024. A non-canonical role of somatic Cyclin D/CYD-1 in oogenesis and in maintenance of reproductive fidelity, dependent on the FOXO/DAF-16 activation state. PLoS genetics, 20(11), p.e1011453.
Written by Umanshi Rautela