A speculative outlook on embryonic aneuploidy: Can molecular pathways be involved?

Abstract

The journey of embryonic development starts at oocyte fertilization, which triggers a complex cascade of events and cellular pathways that guide early embryogenesis. Recent technological advances have greatly expanded our knowledge of cleavage-stage embryo development, which is characterized by an increased rate of whole-chromosome losses and gains, mixoploidy, and atypical cleavage morphokinetics. Embryonic aneuploidy significantly contributes to implantation failure, spontaneous miscarriage, stillbirth or congenital birth defects in both natural and assisted human reproduction. Essentially, early embryo development is strongly determined by maternal factors. Owing to considerable limitations associated with human oocyte and embryo research, the use of animal models is inevitable. However, cellular and molecular mechanisms driving the error-prone early stages of development are still poorly described. In this review, we describe known events that lead to aneuploidy in mammalian oocytes and preimplantation embryos. As the processes of oocyte and embryo development are rigorously regulated by multiple signal-transduction pathways, we explore the putative role of signaling pathways in genomic integrity maintenance. Based on the existing evidence from human and animal data, we investigate whether critical early developmental pathways, like Wnt, Hippo and MAPK, together with distinct DNA damage response and DNA repair pathways can be associated with embryo genomic instability, a question that has, so far, remained largely unexplored.

Molecular Contribution to Embryonic Aneuploidy and Genotypic Complexity During Initial Cleavage Divisions of Mammalian Development

“…Given that inappropriate expression of maternally-inherited signaling factors has been suggested to regulate early mitotic chromosome segregation in mammalian preimplantation embryos (Mantikou et al, 2012; Taylor et al, 2014; Tsuiko et al, 2019), we next determined whether BUB1B deficiency impacted the expression of other key genes ( Fig. 1A ).…”

“…This is in spite of findings that mitotic errors are equally or more prevalent than meiotic errors and arise independently of maternal age or fertility status (Chavez et al, 2012; Chow et al, 2014; McCoy, Demko, Ryan, Banjevic, Hill, Sigurjonsson, Rabinowitz, Fraser, et al, 2015; McCoy, Demko, Ryan, Banjevic, Hill, Sigurjonsson, Rabinowitz, & Petrov, 2015; Vanneste et al, 2009). Since the first three mitotic divisions are the most error-prone and activation of the embryonic genome does not occur until the 4- to 8-cell stage in the majority of mammals (Braude, Bolton, & Moore, 1988; Dobson et al, 2004; Plante, Plante, Shepherd, & King, 1994), it was suggested that maternally-inherited signaling factors regulating early mitotic chromosome segregation may be lacking or compromised in mammalian preimplantation embryos (Mantikou, Wong, Repping, & Mastenbroek, 2012; Taylor et al, 2014; Tsuiko et al, 2019).…”

SAC during early cell divisions: Sacrificing fidelity over timely division, regulated differently across organisms

“…On the other hand, mammalian species such as human [ 11,76,77 ] non‐human primates [ 78,79 ] , farm animals [ 80–84 ] and murine [ 74 ] have been reported to have chromosomal mosaicism in pre‐implantation embryos. [ 85 ] Their reproductive strategy involves longer gestation times with fewer progeny. So why not have an efficient mechanism in place guarding chromosomal behavior in order to increase the chances of viable offspring?…”

Polyploidy of semi-cloned embryos generated from parthenogenetic haploid embryonic stem cells

“…Proper segregation of both maternal and paternal haploid chromosome sets into each blastomere is required at the first division of the zygote to form a developmentally competent 2-cell embryo. Otherwise, developmental defects arise in embryos due to aneuploidy or polyploidy [19]. Polyploidy describes genomes with more than two complete sets of chromosomes, and is observed in several species including plants and yeasts [20].…”