PARENT SESSION
MINISYMPOSIUM XII: Regulation of the Meiotic Cell Cycle
Wednesday, August 1, 2001, 10:00 AM-12:00 PM
Westin-Confederation II
Chair: Mary Ann Handel
Speakers: Gary J Gorbsky, Mary Ann Handel, John J Eppig

MEIOSIS IN THE FEMALE MOUSE: LESSONS LEARNED FROM MEIOTIC ABNORMALITIES.

Eppig, John¹, Schimenti, John¹, Libby, Brian¹, De La Fuente, Rabindranath¹, Viveiros, Maria¹, ¹

ABSTRACT- The progression of meiosis in oocytes is a caricature of the cell cycle with unique stops and starts. These features provided the basis for initial experimentation using oocytes of frogs and various invertebrates, which, in combination with yeast genetics, led to the discovery of several of the fundamental molecules that drive the cell cycle. Similarly, mutations are a valuable tool for revealing basic biological processes because the resultant abnormal phenotypic effects help connect genes with functions. Here we describe studies on two model systems, one spontaneous and one from a mutagenesis program, that display abnormalities in the progression of oocyte meiosis in mice. Oocytes of strain LT mice display a prolonged metaphase I (MI) and many of these oocytes undergo subsequent spontaneous parthenogenetic activation. The prolonged MI is associated with sustained p34cdc2 activity and restricted cyclin B degradation. Since treatment of normal oocytes with protein kinase C (PKC) agonists inhibits the transition to MII, mimicking the LT phenotype, LT oocytes were treated with the specific PKC inhibitor bisindolylmaleimide I (BIM). p34cdc2 kinase activity was transiently reduced by BIM, and progression to MII was promoted, while MAPK activity remained elevated during the MI to MII transition. Confocal microscopy analysis of LT oocytes during this transition showed that the PKC-delta isoform associated first with the meiotic spindle and then with the chromosomes at MII. Inhibition of PKC activity also prevented untimely entry into interphase, but only when PKC activity was reduced in oocytes before the progression to MII. Hence, the transition into interphase is directly associated with the delayed triggering of anaphase I. Thus, PKC participates in the regulatory mechanisms that delay entry into anaphase I in LT oocytes and this delay promotes parthenogenetic activation. The fundamental lesson learned from these experiments is that loss of regulatory control over PKC activity disrupts the critical MI to MII transition during oocyte maturation and can lead to a precocious exit from meiosis and parthenogenetic activation. These studies of the LT mice provide an impetus to investigate the normal role of PKC during oocyte maturation, which at present is poorly understood. Spontaneous mutations affecting oocyte development are rarely discovered. However, the technology now exists for the induction and screening of mutations on a large scale, providing a powerful tool for the search for such genes. One such mutation, mei1, was discovered in a screen for infertile males in a mutagenesis program. Although no sperm are produced in the males, the ovaries contain a reduced number of oocytes that appear to undergo normal growth. However, the progression of meiosis in oocytes is clearly abnormal. Although normally bivalents are aligned on the metaphase I spindle of fully-grown oocytes, mei1 oocytes attempt to align univalents, but the alignment is disorganized. In some oocytes a futile segregation of univalents at anaphase I occurs. As in spermatogenesis, synapsis is defective during early meiosis in mei1 oocytes. However, the early prophase arrest that aborts further gamete development during spermatogenesis does not occur efficiently in oocytes.

KEY WORDS: meiosis, oocyte development