G6PC3 is involved in spermatogenesis by maintaining meiotic sex chromosome inactivation

Abstract

Meiosis, a process unique to germ cells, involves formation and repair of double-stranded nicks in DNA, pairing and segregation of homologous chromosomes, which ultimately achieves recombination of homologous chromosomes. Genetic abnormalities resulted from defects in meiosis are leading causes of infertility in humans. Meiotic sex chromosome inactivation (MSCI) plays a crucial role in the development of male germ cells in mammals, yet its underlying mechanisms remain poorly understood. In this study, we illustrate the predominant presence of a protein known as glucose 6 phosphatase catalyzed 3 (G6PC3) in pachytene spermatocytes, with a high concentration in the sex body (XY body), suggesting its significant involvement in male germ cell development. By employing CRISPR-Cas9 technology, we generate mice deficient in the G6pc3 gene, resulting in complete meiotic arrest at the pachytene stage in spermatocytes and are completely sterile. Additionally, we observe abnormal XY body formation and impaired MSCI in G6pc3-knockout spermatocytes. These findings underscore G6pc3 as a new essential regulator that is essential for meiotic progression. G6PC3 is involved in spermatocyte during male spermatogenesis development by the maintenance of meiosis chromosome silencing.

1. Introduction

To create haploid gametes, both paternal and maternal germ cells undergo a process called meiosis, which is characterized by the pairing and exchange of genetic material between their corresponding chromosomes [1]. The accuracy of meiosis is tightly regulated by checkpoint mechanisms, ensuring that cells with faulty chromosome pairing are eliminated to prevent the production of gametes with an incorrect number of chromosomes [2]. In male meiosis, sex chromosomes form a specialized structure known as the sex body (XY body), where they undergo widespread transcriptional silencing, a phenomenon referred to as meiotic sex chromosome inactivation (MSCI) [3]. MSCI is a critical event in male germ cell development because of the evolution of distinct sex chromosomes in mammals [4].

Many important components involved in MSCI have been identified, including sensing proteins such as SYCP3, HORMAD1, HORMAD2, and BRCA1, as well as effector molecules such as MDC1 and histone γH2AX [5–8]. Despite the well-established link between impaired MSCI and meiotic defects leading to germ cell elimination, the specific mechanisms underlying this process remain poorly understood.

Glucose 6 phosphatase catalyzed 3 (G6PC3) is a significant membrane protein found in the endoplasmic reticulum that consists of 9 transmembrane regions [9]. The active site of the catalytic subunit of glucose-6-phosphatase faces the interior of the endoplasmic reticulum, while the glucose-6 phosphatase (G6P) transporter facilitates the transport of G6P molecules from the cytoplasm to the catalytic subunit’s active site [10]. G6PC3 is implicated in various physiological processes, such as cardiovascular function, urogenital health, neutropenia, and even testicular failure [11]. G6PC3 is highly conserved across various species [12], However, its role in reproductive development has not been fully elucidated.