From fertilization to cancer: The role of centrosomes in the union and separation of genomic material

Centrosomes play crucial roles in the union of sperm and egg nuclei during fertilization and in the equal separation of genomic material during cell d ivision, While many studies in recent years have focused on the molecular c omposition of centrosomes, this article focuses on the structural behavior of centrosomes and on factors that play a role in centrosome functions unde r normal, artificially altered, and abnormal conditions. We review here how studies in the classic sea urchin egg model have contributed to our knowle dge on the centrosome cycle within the cell cycle, on compaction and decomp action of centrosomal material, and on the contributions of maternal and pa ternal centrosomes during fertilization. Centrosome material is activated i n unfertilized eggs by increasing pH with ammonium and by increasing calciu m with the ionophore A23187, which are conditions that are normally induced by sperm. D2O and taxol also induce centrosome aggregation in the unfertil ized egg. Maternal and paternal centrosome material both contribute to the formation of a functional centrosome but the formation of a bipolar centros ome requires material from the paternal centrosome. Fertilization of taxol- treated eggs reveals that the male centrosome possesses the capability to a ttract maternal centrosome material. When pronuclear fusion of the male and female pronuclei is inhibited with agents such as the disulfide reducing a gent dithiothreitol (DTT) a bipolar mitotic apparatus is formed fi om the p aternal centrosome. Furthermore, one centrosome of the bipolar mitotic appa ratus is capable of organizing an additional half spindle that attaches to the female pronucleus indicating a functional and perhaps structural connec tion between centrosomes and chromatin. Sea urchin eggs are also useful to study centrosome abnormalities and consequences for the cell cycle. While c lassic studies by Theodor Boveri have shown that dispermic fertilization wi ll result in abnormal cell division because of multiple centrosomes contrib uted by sperm, abnormal cell division can also be induced by chemical alter ations of centrosomes. Compaction and decompaction of centrosome structure is studied using chloral hydrate or the chaotropic agent formamide, which r eveals that centrosomes can be chemically altered to produce mono- or multi polar abnormal mitosis and unequal distribution of genomic material upon re lease from formamide. The patterns of abnormal centrosome reformations afte r recovery from formamide treatment resemble those seen in cancer cells whi ch argues that structural defects of centrosomes can account for the format ion of abnormal mitosis and multipolar cells frequently observed in cancer. Tn summary, the sea urchin model has been most useful to gain information on the role of centrosomes during fertilization and cell division as well a s on adverse conditions that play a role in centrosome dysfunctions and in disease. (C) 2000 Wiley-Liss.