Role of Filia, a maternal effect gene, in maintaining euploidy during cleavage-stage mouse embryogenesis

Proc Natl Acad Sci U S A. 2009 May 5;106(18):7473-8. doi: 10.1073/pnas.0900519106. Epub 2009 Apr 17.

Abstract

During oogenesis, mammalian eggs accumulate proteins required for early embryogenesis. Although limited data suggest a vital role of these maternal factors in chromatin reprogramming and embryonic genome activation, the full range of their functions in preimplantation development remains largely unknown. Here we report a role for maternal proteins in maintaining chromosome stability and euploidy in early-cleavage mouse embryogenesis. Filia, expressed in growing oocytes, encodes a protein that binds to MATER and participates in a subcortical maternal complex essential for cleavage-stage embryogenesis. The depletion of maternal stores of Filia impairs preimplantation embryo development with a high incidence of aneuploidy that results from abnormal spindle assembly, chromosome misalignment, and spindle assembly checkpoint (SAC) inactivation. In helping to ensure normal spindle morphogenesis, Filia regulates the proper allocation of the key spindle assembly regulators (i.e., AURKA, PLK1, and gamma-tubulin) to the microtubule-organizing center via the RhoA signaling pathway. Concurrently, Filia is required for the placement of MAD2, an essential component of the SAC, to kinetochores to enable SAC function. Thus, Filia is central to integrating the spatiotemporal localization of regulators that helps ensure euploidy and high-quality cell cycle progression in preimplantation mouse development. Defects in the well-conserved human homologue could play a similar role and account for recurrent human fetal wastage.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Aurora Kinase A
  • Aurora Kinases
  • Cell Cycle Proteins / metabolism*
  • Cleavage Stage, Ovum / cytology
  • Cleavage Stage, Ovum / physiology*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / physiology*
  • Embryonic Development
  • Female
  • Mad2 Proteins
  • Mice
  • Mice, Mutant Strains
  • Ploidies*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / physiology*
  • Proto-Oncogene Proteins / metabolism
  • Spindle Apparatus / metabolism*
  • Tubulin / metabolism

Substances

  • Cell Cycle Proteins
  • Mad2 Proteins
  • Mad2l1 protein, mouse
  • Proteins
  • Proto-Oncogene Proteins
  • Tubulin
  • filia protein, mouse
  • AURKA protein, human
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1