Characterizing hematological and reproductive phenotypes in the Plk4+/– mouse

The polo-like kinases (Plks) are a family of serine/threonine kinases, of which there are five members. These protein kinases are involved in a multitude of processes associated with the cell cycle. These include centriole duplication, maturation of centrosomes, mitotic entry, and cytokinesis. Since the Plks are involved in such critical processes, dysregulation of these proteins are implicated in the development of a variety of malignancies. Higher and lower levels of Plk4 are both associated with tumourigenesis, therefore Plk4 can act as either an oncogene or tumour suppressor. While Plk4–/– mice are embryonic lethal, Plk4+/– mice are viable. Aged Plk4+/– mice develop hepatocellular carcinoma at a higher incidence than wild-type littermates and there is evidence that PLK4 levels are lower in human hematological malignancies. A complete picture of all the phenotypes associated with lower PLK4 levels remains. Therefore, we sought to investigate further in the Plk4+/– mouse. Based on the observations in human hematological malignancies, we hypothesized that Plk4 heterozygosity may result in hematological changes in the mouse. Therefore, the bulk of the work in this dissertation went toward investigating a hematological phenotype in the Plk4+/– mouse model. Hematopoiesis is the generation of new blood cells originating from the hematopoietic stem cell. Here, I show that aged Plk4+/– mice exhibit signs of myeloid-biased hematopoiesis in the bone marrow and a concomitant increase in splenic erythropoiesis. Those Plk4+/– mice that develop enlarged spleens display a further expansion of myeloid cells in both the bone marrow and spleen. These mice possess an increase in myeloid potential at the expense of lymphoid and erythroid development, exhibiting signs of a myeloproliferative neoplasm. This work suggests that normal levels of Plk4 are important in maintaining hematopoietic homeostasis in the mouse. Furthermore, Plk4 mutations have been identified that have been linked to human and mouse infertility in males and females. We therefore hypothesized that the Plk4+/– mouse would also display signs of subfertility. We thus investigated the effect of lower Plk4 levels in the Plk4 transgenic mouse model. Male Plk4+/– mice display a higher incidence of seminiferous tubule round spermatid arrest. Female Plk4+/– mice display signs of impaired ovarian follicle development. These results are likely related to the observation of a reduction in litter size from matings featuring one Plk4+/– parent