Genetic causes of preimplantation embryo developmental failure

Abstract

Embryo development requires orchestrated events, finely regulated at the molecular and cellular level by mechanisms which are progressively emerging from animal studies. With progress in genetic technologies—such as genome editing and single‐cell RNA analysis—we can now assess embryo gene expression with increased precision and gain new insights into complex processes until recently difficult to explore. Multiple genes and regulative pathways have been identified for each developmental stage. We have learned that embryos with undisturbed and timely gene expression have higher chances of successful development. For example, selected genes are highly expressed during the first stages, being involved in cell adhesion, cell cycle, and regulation of transcription; other genes are instead crucial for lineage specification and therefore expressed at later stages. Due to ethical constraints, studies on human embryos remain scarce, mainly descriptive, and unable to provide functional evidence. This highlights the importance of animal studies as basic knowledge to test and appraise in a clinical context. In this review, we report on preimplantation development with a focus on genes whose impairment leads to developmental arrest. Preconceptional genetic screening could identify loss‐of‐function mutations of these genes; thereby, novel biomarkers of embryo quality could be adopted to improve diagnosis and treatment of infertility.

Molecular Drivers of Developmental Arrest in the Human Preimplantation Embryo: A Systematic Review and Critical Analysis Leading to Mapping Future Research

“…The introduction of TLM has enabled continuous monitoring, thus abnormal developmental patterns are easily detectable [ 30 ]. The development of whole genome sequencing techniques has enabled not only a more accurate characterization of embryo ploidy but has assisted in providing substantial information regarding the gene variations that may hinder embryonic development [ 32 ]. It has been voiced that null-mutations and differential gene expression may be a more frequent cause of embryonic developmental arrest [ 32 ].…”

“…The development of whole genome sequencing techniques has enabled not only a more accurate characterization of embryo ploidy but has assisted in providing substantial information regarding the gene variations that may hinder embryonic development [ 32 ]. It has been voiced that null-mutations and differential gene expression may be a more frequent cause of embryonic developmental arrest [ 32 ]. The early and accurate assessment of the developmental potential of the human embryo is of added value especially in countries where duration of embryo cryopreservation may be extended indefinitely [ 31 ].…”

“…These extrinsic factors may be described as techniques employed in the IVF laboratory that gametes and embryos are subjected to, along with conditions of embryo culture This constitutes an equally interesting area of research. Two comprehensive reviews regarding developmental arrest and one systematic review focused on the embryonic abnormal developmental patterns have been recently published [ 30 , 31 , 32 ], indicating the explosion of interest noted on the subject at hand. The present systematic review uniquely provides to literature an original and in-depth critical analysis on available data reporting strictly on intrinsic factors associated with developmental arrest in human embryos and investigating molecular mechanisms and pathways driving developmental arrest.…”

Molecular regulation of trophoblast stem cell self-renewal and giant cell differentiation by the Hippo components YAP and LATS1

“…Although numerous research initiatives have been undertaken to understand Hippo in various tissues and biological processes [ 21 , 22 ], minimal efforts have been undertaken to appreciate Hippo in reproductive biology. Malfunctioning of Hippo components has been associated with defects in TE as well as inner cell mass (ICM) specification leading preimplantation developmental arrest [ 23 , 24 ]. Recently, Hippo has been reported to translate positional information into indispensable transcriptional circuits specifying the trophectoderm in preimplantation embryos [ 25 , 26 ].…”

Control of Maternal-to-Zygotic Transition in Human Embryos and Other Animal Species (Especially Mouse): Similarities and Differences

“…MZT is observed in all animal species investigated so far [ 1 ] including mammals [ 2 ]; it is essential for embryonic development because it coordinates cell division and allocation to the first two cell lineages, i.e., the inner cell mass (ICM) and trophectoderm, at the blastocyst stage [ 3 ]. Even though, so far as human embryos are concerned, there are still a lot of open questions, there is no doubt that failure of MZT is involved in preimplantation embryo demise and the resulting failure of assisted reproduction techniques (ART) [ 4 ]. Knowledge of the molecular mechanisms regulating MZT in humans is thus important for the development of diagnostic methods with which the quality of each individual embryo can be tested and the adequacy of particular ovarian stimulation protocols in each individual woman can be evaluated, enabling an individualized approach [ 5 ].…”