Newswise — A recent research conducted by experts from Uppsala University and INRAE/Université Paris-Saclay has unveiled the vital involvement of ZC3H11A, a pro-viral host protein, in preserving embryo viability in the initial stages of growth. This study has brought to light a previously undisclosed role of ZC3H11A in the complex mechanism of embryonic development and emphasizes its influence on growth. The findings of this investigation are published in the Proceedings of the National Academy of Sciences (USA).

With a vast repertoire of over twenty thousand genes within the human body, the precise physiological roles of numerous genes remain shrouded in mystery. In a previous investigation conducted by the same group, the identification of ZC3H11A (abbreviated as ZC3) as a pro-viral protein shed light on its indispensable role in facilitating the robust proliferation of several nuclear-replicating viruses that afflict humans, such as HIV. Consequently, the ZC3 protein has emerged as a promising target for the development of antiviral agents against medically significant human viruses. In their current study, the research team has unveiled an additional function of ZC3 that manifests during a specific phase of early embryo growth in mice. Intriguingly, upon removing ZC3 from adult mouse tissues, no discernible abnormalities were observed, implying that ZC3 exhibits distinct functions contingent upon the developmental stage.

The latest investigation has conclusively established the pivotal involvement of ZC3 in overseeing the expression of metabolic genes that are pivotal for the metabolic alterations witnessed in embryos during the implantation phase. The absence or disturbance of ZC3 leads to absolute lethality in mouse embryos, and it is highly probable that inactivation of this gene would have similar consequences in other mammals, including humans. This discovery underscores the irreplaceable significance of ZC3 in orchestrating the fundamental metabolic mechanisms that are crucial for the viability and progression of embryonic development.

Shady Younis, the lead researcher of the study conducted in collaboration with Leif Andersson at the Department of Medical Biochemistry and Microbiology, Uppsala University, elucidates the objective of establishing a mouse model with a ZC3 deficiency to investigate its significance in virus replication. To their surprise, the team discovered that mouse embryos lacking a functional ZC3 gene could not survive. Consequently, they made the decision to examine ZC3 knock-out mouse embryos at different stages of development to identify the exact timeframe during which ZC3 plays a critical role.

Through the application of RNA-sequencing and proteomics assays, the research team achieved a significant breakthrough concerning embryos devoid of ZC3. Their investigations unveiled pronounced abnormalities in metabolic regulation within these embryos. This finding sheds light on the crucial involvement of ZC3 in orchestrating the intricate balance of metabolic processes during embryonic development.

Alice Jouneau, a co-author of the study and an embryologist from INRAE/Université Paris-Saclay, highlights the methodology employed in the research. Mouse embryos at early stages of pregnancy were collected with the specific objective of identifying ZC3-null embryos for comprehensive examination. During the analysis, a portion of the embryos exhibited morphological abnormalities. Subsequent DNA genotyping verified that these embryos were indeed devoid of the ZC3 gene, providing further evidence of the link between ZC3 deficiency and the observed developmental defects.

Undeterred by the embryonic lethality observed in association with ZC3 deletions, the researchers embarked on a study to investigate the repercussions of ZC3 deletion in adult organs. To accomplish this, they devised an inducible mouse model that facilitated the targeted elimination of ZC3 specifically after birth. Surprisingly, the findings of this investigation unveiled an unexpected outcome: complete inactivation of ZC3 in mouse tissues did not manifest any discernible effects on cell growth or viability. The absence of noticeable clinical consequences following ZC3 depletion in adult tissues implies that an anti-viral therapy centered around ZC3 inactivation might not yield significant side effects. This discovery opens up promising prospects for the development of anti-viral treatments exploiting ZC3 as a therapeutic target.

Leif Andersson, a Professor of Functional Genomics at Uppsala University, emphasizes the significance of ZC3H11A as a highly conserved gene present in various vertebrates, yet with a relatively unclear function. The current study provides valuable insights into the functional importance of ZC3, highlighting its critical role in normal embryonic development. Andersson further emphasizes that while ZC3 does not seem to be essential for cellular growth after birth, its involvement in the replication of multiple medically significant viruses makes it a captivating target for the development of novel anti-viral therapies. This finding paves the way for potential advancements in combating viral infections through targeted interventions that exploit the unique characteristics of ZC3.

 Image 1: Schematic illustration demonstrating different stages of embryo development, highlighting the time-point of implantation with an arrow. Embryos lacking the ZC3H11A protein are unable to survive after implantation, resulting in their degeneration.

Journal Link: Proceedings of the National Academy of Sciences