Esx1, an X-linked homeobox gene, has diverse functions. In mammals, its expression is restricted to extraembryonic tissues during embryogenesis, such as the endoderm of the visceral yolk sac, the ectoderm of the chorion, and the labyrinthine trophoblast of the chorioallantoic placenta. In adults, it is detected only in testes, specifically in pre-and post-meiotic germ cells [4,6]. It is potentially involved in regulating fetal-maternal interactions during placental development and male germ cell development [6].

In the context of male infertility, genetic factors like variants in Esx1 are associated with non-obstructive azoospermia (NOA). Whole-genome sequencing has identified Esx1 as a potential candidate gene for NOA [1,7]. Activation of the Esx1 gene using CRISPRa technology in human germ cells (TCam-2) led to the determination of a network of over 50 potentially regulated genes, with 6 genes (NANOG, CXCR4, RPS6KA5, CCND1, PDE1C, and LINC00662) related to cell proliferation and differentiation being verified in azoospermic patients [1]. Also, specific missense and synonymous mutations in Esx1 unique to NOA patients were identified in a Chinese male cohort, with the compound mutant p.[P365R; L366V] ESX1 affecting cyclin A degradation and cell cycle progression [2]. Moreover, ESX1 mRNA expression in seminal fluid can predict residual spermatogenesis in NOA men, serving as a suitable molecular marker [3,5].

In summary, Esx1 is crucial for placental development and male germ cell development. Its study, especially through genetic models, has provided insights into male infertility, particularly NOA. Understanding Esx1's functions and its role in related pathways may offer potential strategies for diagnosing and treating male infertility associated with NOA.

References:

1. Malcher, Agnieszka, Graczyk, Zuzanna, Bauer, Hermann, Yatsenko, Alexander N, Kurpisz, Maciej. 2023. ESX1 gene as a potential candidate responsible for male infertility in nonobstructive azoospermia. In Scientific reports, 13, 16563. doi:10.1038/s41598-023-43854-9. https://pubmed.ncbi.nlm.nih.gov/37783880/

2. Ma, Qian, Du, Ye, Luo, Xiaomin, Ye, Jing, Gui, Yaoting. 2021. Association of ESX1 gene variants with non-obstructive azoospermia in Chinese males. In Scientific reports, 11, 4587. doi:10.1038/s41598-021-84182-0. https://pubmed.ncbi.nlm.nih.gov/33633269/

3. Pansa, Alessandra, Sirchia, Silvia M, Melis, Sara, Miozzo, Monica, Tabano, Silvia. 2014. ESX1 mRNA expression in seminal fluid is an indicator of residual spermatogenesis in non-obstructive azoospermic men. In Human reproduction (Oxford, England), 29, 2620-7. doi:10.1093/humrep/deu261. https://pubmed.ncbi.nlm.nih.gov/25316452/

4. Li, Y, Behringer, R R. . Esx1 is an X-chromosome-imprinted regulator of placental development and fetal growth. In Nature genetics, 20, 309-11. doi:. https://pubmed.ncbi.nlm.nih.gov/9806555/

5. Bonaparte, E, Moretti, M, Colpi, G M, Gallina, A, Miozzo, M. 2010. ESX1 gene expression as a robust marker of residual spermatogenesis in azoospermic men. In Human reproduction (Oxford, England), 25, 1398-403. doi:10.1093/humrep/deq074. https://pubmed.ncbi.nlm.nih.gov/20356899/

6. Li, Y, Lemaire, P, Behringer, R R. . Esx1, a novel X chromosome-linked homeobox gene expressed in mouse extraembryonic tissues and male germ cells. In Developmental biology, 188, 85-95. doi:. https://pubmed.ncbi.nlm.nih.gov/9245514/

7. Malcher, Agnieszka, Stokowy, Tomasz, Berman, Andrea, Yatsenko, Alexander N, Kurpisz, Maciej K. 2022. Whole-genome sequencing identifies new candidate genes for nonobstructive azoospermia. In Andrology, 10, 1605-1624. doi:10.1111/andr.13269. https://pubmed.ncbi.nlm.nih.gov/36017582/