The centrioles are the only cytoplasmic structures provided exclusively by the sperm, to the embryo. Centrioles are microtubule-based organelles that have two critical functions. They form the cell?s cilium (a subcellular mechanism for signaling and motility). And together with the proteinaceous pericentriolar material (PCM), they form the cell?s centrosome (the cell?s major microtubule organization center). Dividing embryonic cells must have precisely two centrioles for healthy development. During sperm formation, the quantity of many centriolar and PCM proteins declines, modifying the structure of one of the sperm centrioles beyond recognition. This process is known as centrosome reduction and is thought to eliminate the PCM and degenerate one of the centrioles, leaving the sperm with one intact centriole. The presence of only one recognizable centriole raises the question, what is the origin of the embryo?s second centriole? Recently, the Avidor-Reiss laboratory determined that the presumed degenerated centriole is unexpectedly maintained, despite structural and protein compositional changes. Furthermore, the Avidor-Reiss lab characterized the sperm neck and found that all centrosomal structures had altered protein compositions. They named the structural changes, protein enrichment, and protein reduction, as Centriole Remodeling. The role and importance of centriole remodeling in humans are poorly understood. However, evidence from the Avidor-Reiss lab argues that remodeling is essential for embryo development in animals. Currently, a significant fraction of reproductive diseases, such as infertility, recurrent miscarriages, and abnormal embryo development, are of unknown cause. Since the Avidor-Reiss lab recently found that the remodeled sperm centrioles function in the zygote, errors in centriole remodeling may be a previously unknown cause for reproductive diseases. Consequently, the long-term goal of the proposed research is to develop a diagnostic test for reproductive diseases caused by sperm centriole defects. The objective of this application is to determine the first set of centriole remodeling markers that are associated with defective sperm. The central hypothesis of our research is that abnormal levels of centriole remodeling proteins in the spermatozoon can cause reproductive diseases.
The specific aim of this application is to identify centriolar markers that are associated with abnormal sperm morphology and infertility. This research is conceptually innovative because it is the first study that aims to identify centriole remodeling proteins for the diagnosis of reproductive diseases. The rationale is that the identification of diagnostic markers that are involved in centriole remodeling will provide an essential step towards identifying new causes of reproductive diseases. Ultimately, knowledge gained from this research has the potential to improve the diagnosis and treatment of diseases such as idiopathic male infertility, early pregnancy loss, and embryo development defects.
The genetics of reproductive diseases such as idiopathic male infertility, early pregnancy loss, and embryonic defects are poorly understood. The goal of this project is to screen paternal centriolar proteins to identify molecular markers that are associated with defective sperm and that may cause reproductive diseases.