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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2238-2247
HEMATOPOIESIS
Asymmetrical segregation of chromosomes with a normal
metaphase/anaphase checkpoint in polyploid megakaryocytes
Lydia Roy,
Philippe Coullin,
Natacha Vitrat,
Raymond Hellio,
Najet Debili,
Jasminder Weinstein,
Alain Bernheim, and
William Vainchenker
From the Institut National de la Santé et de la
Recherche Médicale (INSERM) U362; Unité Mixte de Recherche
and Centre National de Recherche Scientifique (UMR 1599); Institut
Gustave Roussy, Villejuif, France; Station de Microscopie Confocale,
Institut Pasteur, Paris, France; and Amgen, Thousand Oaks, CA.
During differentiation, megakaryocytes increase ploidy through a
process called endomitosis, whose mechanisms remain unknown. As it
corresponds to abortive mitosis at anaphase and is associated with a
multipolar spindle, investigation of chromosome segregation may help to
better understand this cell-cycle abnormality. To examine this
variation, a new method was developed to combine primed in situ
labeling to label centromeres of one chromosome category and
immunostaining of tubulin. Human megakaryocytes were obtained from
normal bone marrow culture. By confocal microscopy, this study
demonstrates an asymmetrical distribution of chromosomes (1 or 7)
either between the spindle poles at anaphase stage of endomitosis and
between the different lobes of interphase megakaryocyte nuclei. The
metaphase/anaphase checkpoint appears normal on the evidence that under
nocodazole treatment megakaryocytes progressively accumulate in
pseudo-metaphase, without spontaneous escape from this blockage.
Immunostaining of p55CDC/hCDC20 with similar kinetochore localization
and dynamics as during normal mitosis confirms this result. HCdh1 was
also expressed in megakaryocytes, and its main target, cyclin B1, was
normally degraded at anaphase, suggesting that the
hCdh1-anaphase-promoting complex checkpoint was also functional. This
study found the explanation for these unexpected results of an
asymmetrical segregation coupled to normal checkpoints by careful
analysis of multipolar endomitotic spindles: whereas each aster is
connected to more than one other aster, one chromosome may segregate
symmetrically between 2 spindle poles and still show asymmetrical
segregation when the entire complex spindle is considered.
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