Developing an animal model to identify the role of the sperm centriole in fertility

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Somatic cells require two centrioles that each form one of the spindle poles of dividing cells. In contrast, the zygotes of insects and many mammals, including humans, are thought to have only a single centriole, which is of paternal origin. The Avidor-Reiss lab has identified a second, atypical centriole of paternal origin in insect zygotes that is essential for normal embryo development. More importantly, they have acquired new data suggesting that, like in insects, the spermatozoa of humans and many other mammalian species have an atypical centriole that may also be paternally inherited. Consequently, the long-term goal of the proposed research is to reveal the unique properties of these atypical sperm centrioles, specifically their conservation, unique biochemistry, function, and contribution to fertilization and embryo development. The objective of this application is to (1) test if the distal centriole of mammalian sperm, which is thought to be “degenerated” and functionally dead, is actually an “atypical” centriole that is essential after fertilization and (2) to develop a mammalian model system to study the role of this “degenerated” distal centriole during embryo development. Data from the Avidor-Reiss lab indicates that mammalian spermatozoa contain, in addition to the typical centriole (known as the proximal centriole), an atypical centriole (the “degenerated” distal centriole). These data suggest that the distal centriole is not degenerated, but rather remodeled. This atypical centriole lacks the structural characteristics of a centriole, but contains core centriolar proteins. Therefore, the central hypothesis is that, like the proximal centriole, the remodeled distal centriole (RDC) forms one of the two zygotic centrosomes after fertilization and one of the spindle poles when the zygote divides. The rationale is that the identification of the RDC as the mammalian second zygotic centriole will direct studies of its role in male infertility and early pregnancy loss. The rabbit is an excellent model for these studies because rabbit zygotes, like humans, require sperm centrioles. Our specific aim is to determine the origin, number, and structure of the centrioles in the rabbit zygote. This research is innovative because it is the first to examine a revolutionary hypothesis on the origin of the second zygotic centriole, using a mammalian model specifically designed for this purpose. This study is expected to advance the understanding of centriolar function in fertility. Ultimately, knowledge gained from this basic research will form a basis for additional insights into potential new causes of male infertility, early stage miscarriages, and developmental diseases.