During female meiosis, of the chromosomes are eliminated and only of the chromosomes are inherited by a single egg. In contrast, all chromosomes are distributed among 4 sperm during male meiosis. The elimination of of the genome to allow inheritance of only of the chromosomes is conserved in all animal phyla, suggesting some fundamental selective advantage. The long-term goals of this project are to elucidate the molecular mechanisms of chromosome elimination and elucidate the selective advantages of asymmetric meiotic division. Errors in meiosis lead to the absence of one chromosome (monosomy) or the presence of an extra chromosome (trisomy) in 10-30% of human conceptions with the majority of these aneuploidies leading to embryonic death. By elucidating the mechanisms of meiotic chromosome elimination in C. elegans, we will identify mechanisms likely to be defective during human meiosis. Fertilization occurs during female meiosis in nearly all animal species. Therefore, animals must have mechanisms to prevent incorporation of paternal chromosomes into the meiotic spindle which could eliminate paternal chromosomes in a polar body causing lethal monosomy. We have demonstrated that, in C. elegans, microtubule driven transport moves the meiotic spindle to a cortical position away from the future site of fertilization, and that the sperm contents are immobilized at the distant site of fertilization by cortical actin. Cortical positioning of the meiotic spindle and sperm contents at opposite ends of the zygote resists cytoplasmic streaming which circulates membranous organelles around the zygote. Actin depolymerization results in movement of a cohesive unit containing sperm-derived DNA, centrioles, mitochondria and other membranous organelles with cytoplasmic streaming. However, the resulting collisions between the sperm contents and meiotic spindle do not result in incorporation of paternal chromosomes into the meiotic spindle. We seek to elucidate the completely unexplored mechanism that holds the sperm contents together as a cohesive unit, as this is both required to allow tethering to cortical actin far from the spindle and, as a backup mechanism, insulates paternal chromosomes from capture into the meiotic spindle. We have uncovered a second selective advantage of asymmetric meiosis by demonstrating that extra chromosomes present in trisomic or triploid C. elegans are preferentially deposited in a polar body. We seek to determine the mechanisms that preferentially move extra chromosomes toward the polar body. These mechanisms allow triploid or aneuploid C. elegans to have a high frequency of offspring with a normal chromosome number and could be relevant to the health prospects for offspring of women with triploX syndrome, trisomy 21 or mosaic trisomy. In addition, we will continue to elucidate the katanin, kinesin and dynein-dependent mechanisms ensuring bipolar meiotic spindle assembly and positioning. We will accomplish these goals by directly monitoring the movements of chromosomes and organelles by time-lapse imaging of zygotes observed in utero within transparent C. elegans after perturbations by RNA interference, auxin-induced degrons and optogenetic manipulations.
The proposed research is relevant to public health because chromosomes are missing or an extra chromosome is present in 10-30% of human conceptions. The majority of these chromosomal abnormalities are caused by defects during female meiosis and these chromosomal abnormalities lead to embryonic death or cognitive disability. The proposed research will reveal mechanisms that may cause these abnormalities in humans and will suggest ways to prevent them.
