Multinucleation in the Human Embryo's First Mitosis: Linking Spindle Geometry Defects, SAC Tolerance, Chromosome Segregation, and Nuclear Envelope Reassembly.

Background: Multinucleation occurs at high frequency during the first mitosis of human embryos and is associated with impaired developmental potential. Our live-imaging analyses showed that collapse of spindle geometry-such as low-aspect ratio spindles and pole defocusing-correlates with multinucleation, yet molecular links from aberrant spindle shape to multinucleation remain poorly defined. Methods: We performed a narrative review of published studies on spindle geometry control, kinetochore-microtubule attachment and error correction, spindle assembly checkpoint (SAC) signaling in oocytes and cleavage-stage embryos, chromosome transport, and telophase nuclear assembly, and organized the evidence to outline plausible mechanistic routes to multinucleation. Results: We propose that spindle-geometry defects increase kinetochore-microtubule misattachments and promote spatial dispersion of chromosomes. In early embryos, SAC signaling may limit the time window for correcting these errors, permitting anaphase onset with residual misattachments. In large embryonic cells (cleavage-stage blastomeres far larger than somatic cells), dispersed chromatin may be inefficiently reintegrated during telophase and incompletely enclosed during nuclear assembly, increasing the likelihood of persistent multinucleation. Conclusion: This review provides an integrated perspective linking spindle-shape failure to multinucleation during the first mitosis in human embryos, thereby informing mechanistic studies and contributing to advances in reproductive medicine and infertility treatment outcomes.