Autophagy Protein ATG14 Safeguards Oviduct Function to Enable Embryo Transport During Early Pregnancy

Core Concepts

ATG14 is critical for maintaining the structural integrity and cellular plasticity of the oviduct, preventing unscheduled pyroptosis activation, and enabling the timely transport of embryos from the oviduct to the uterus for successful implantation.

Abstract

The study investigates the role of the autophagy protein ATG14 in female reproductive tract function, particularly in the oviduct. The authors generated a conditional knockout (cKO) mouse model to ablate Atg14 in the female reproductive tract and found that the loss of Atg14 resulted in infertility despite normal ovarian function.
Further analysis revealed that Atg14 cKO mice had impaired embryo implantation and uterine receptivity, as well as a failure in embryo transport from the oviduct to the uterus. Mechanistically, the loss of Atg14 in the oviduct led to severe structural abnormalities, compromising the cellular plasticity and integrity of the oviduct. This was accompanied by the activation of unscheduled pyroptosis, an inflammatory form of cell death, which impeded the smooth transport of embryos through the oviduct.
Interestingly, the selective loss of Atg14 in oviduct ciliary epithelial cells did not impact female fertility, suggesting that the role of Atg14 in maintaining oviduct homeostasis is distinct from its function in cilia. The authors further demonstrated that pharmacological activation of pyroptosis in pregnant mice led to an impairment in embryo transport, corroborating the critical role of Atg14 in safeguarding against unscheduled pyroptosis to enable successful embryo transport.
These findings provide important insights into the cellular mechanisms underlying early pregnancy loss and suggest the potential use of autophagy modulators as novel prevention strategies for reproductive disorders associated with oviduct dysfunction.

Stats

Atg14 cKO females did not deliver any litter during the 6-month breeding trial, while control females delivered an average of 7-8 pups per litter every month.
In Atg14 cKO mice, only 1-2% of embryos were retrieved from the uterus on day 4 of pregnancy, compared to 100% in control mice.
Approximately 80-90% of blastocysts were retrieved from the oviducts of Atg14 cKO mice, while in control mice, 90% of embryos were able to reach the uterus.

Quotes

"Atg14 cKO females did not deliver any litter during 6-months trial period."
"In cKO mice, we could retrieve only 1-2% of embryos from their uteri, whereas in control mice, 100% of well-developed blastocysts were retrieved from their uteri."
"Oviduct flushing from cKO mice resulted in the retrieval of approximately 80-90% of blastocysts, suggesting their potential entrapment within the oviducts, impeding their transit to the uterus."

Key Insights Distilled From

The autophagy protein, ATG14 safeguards against unscheduled pyroptosis activation to enable embryo transport during early pregnancy

by POPLI,P., Oe... at www.biorxiv.org 03-21-2024

https://www.biorxiv.org/content/10.1101/2024.03.19.585812v1

Deeper Inquiries

How might the findings from this study be leveraged to develop novel therapeutic strategies for addressing oviduct-related infertility and early pregnancy loss in humans?

The findings from this study provide valuable insights into the role of ATG14 in maintaining oviductal homeostasis and enabling smooth embryo transport. Leveraging these findings, novel therapeutic strategies could be developed to address oviduct-related infertility and early pregnancy loss in humans. One potential approach could involve the development of targeted therapies that aim to modulate autophagy pathways specifically in the oviduct. By targeting ATG14 or other autophagy-related proteins involved in oviduct function, it may be possible to restore proper cellular plasticity and integrity in the oviduct, thereby improving embryo transport and reducing the risk of pregnancy loss. Additionally, strategies that focus on regulating pyroptosis activation in the oviduct, similar to the role of ATG14 in preventing unscheduled pyroptosis, could also be explored as a therapeutic avenue.

What other cellular pathways or signaling mechanisms might be involved in the regulation of oviduct function and embryo transport, beyond the role of ATG14 and pyroptosis?

In addition to the role of ATG14 and pyroptosis, several other cellular pathways and signaling mechanisms may play a crucial role in the regulation of oviduct function and embryo transport. One such pathway is the ciliary signaling pathway, which is essential for ciliary beat and the transport of embryos through the oviduct. Disruption of ciliary function can lead to impaired embryo transport and infertility. Hormonal signaling pathways, including estrogen and progesterone signaling, also play a significant role in regulating oviduct function and preparing the uterus for embryo implantation. Inflammatory pathways, such as NF-kB signaling, may also impact oviductal health and function, potentially affecting embryo transport. Additionally, pathways involved in cellular adhesion, motility, and contractility could influence the movement of embryos through the oviduct.

Could the modulation of autophagy-related proteins, such as ATG14, have broader implications for reproductive health and the management of other gynecological conditions?

Modulation of autophagy-related proteins, including ATG14, could indeed have broader implications for reproductive health and the management of various gynecological conditions. Autophagy plays a critical role in maintaining cellular homeostasis, regulating inflammation, and ensuring proper cellular function. Dysregulation of autophagy has been implicated in various reproductive disorders, including endometriosis, polycystic ovary syndrome, and infertility. By targeting autophagy-related proteins like ATG14, it may be possible to restore normal cellular function, reduce inflammation, and improve reproductive outcomes. Additionally, since autophagy is involved in various cellular processes beyond reproduction, modulating autophagy pathways could have implications for managing other gynecological conditions, such as ovarian cysts, uterine fibroids, and endometrial disorders. Further research into the role of autophagy in gynecological health could uncover new therapeutic targets and treatment strategies for a range of conditions.