Asunto(s)
Infertilidad , Humanos , Femenino , Infertilidad/terapia , Infertilidad/diagnóstico , Masculino , Técnicas Reproductivas AsistidasRESUMEN
Accurate chromosome segregation during meiosis is crucial for reproduction. Human and porcine oocytes transiently cluster their chromosomes before the onset of spindle assembly and subsequent chromosome segregation. The mechanism and function of chromosome clustering are unknown. Here we show that chromosome clustering is required to prevent chromosome losses in the long gap phase between nuclear envelope breakdown and the onset of spindle assembly, and to promote the rapid capture of all chromosomes by the acentrosomal spindle. The initial phase of chromosome clustering is driven by a dynamic network of Formin-2- and Spire-nucleated actin cables. The actin cables form in the disassembling nucleus and migrate towards the nuclear centre, moving the chromosomes centripetally by interacting with their arms and kinetochores as they migrate. A cage of stable microtubule loops drives the late stages of chromosome clustering. Together, our data establish a crucial role for chromosome clustering in accurate progression through meiosis.
Asunto(s)
Actinas , Oocitos , Humanos , Animales , Porcinos , Actinas/genética , Actinas/metabolismo , Oocitos/metabolismo , Meiosis/genética , Microtúbulos/metabolismo , Cinetocoros/metabolismo , Segregación Cromosómica , Huso Acromático/genética , Huso Acromático/metabolismo , Mamíferos/metabolismoRESUMEN
Human oocytes are prone to assembling meiotic spindles with unstable poles, which can favor aneuploidy in human eggs. The underlying causes of spindle instability are unknown. We found that NUMA (nuclear mitotic apparatus protein)-mediated clustering of microtubule minus ends focused the spindle poles in human, bovine, and porcine oocytes and in mouse oocytes depleted of acentriolar microtubule-organizing centers (aMTOCs). However, unlike human oocytes, bovine, porcine, and aMTOC-free mouse oocytes have stable spindles. We identified the molecular motor KIFC1 (kinesin superfamily protein C1) as a spindle-stabilizing protein that is deficient in human oocytes. Depletion of KIFC1 recapitulated spindle instability in bovine and aMTOC-free mouse oocytes, and the introduction of exogenous KIFC1 rescued spindle instability in human oocytes. Thus, the deficiency of KIFC1 contributes to spindle instability in human oocytes.
