Developmental transitions of germ cell lineage of the mouse

Abstract

Mammalian germ cells arise during early embryogenesis and migrate to the developing gonad where, under the direction of the somatic environment, they initiate distinct sex-specific developmental programs resulting in the production of egg or sperm. Our understanding of the molecular mechanisms governing many stages of germ cell development has advanced greatly in recent years. However, many aspects of germ cell development remain entirely uncharacterized at the molecular level. In this thesis I will present projects utilizing forward and reverse genetics that generate new points of entry into poorly understood transitions during germ cell development. The X and Y chromosome do not have pairing partners during male meiosis. As a result they become silenced during this time. One mechanism that has been proposed to compensate for inactive X-linked housekeeping genes during male meiosis is X-to-autosome retropositions. We have identified a mutation within an X-to-autosome retrogene in the mouse spermatogenic mutant jsd/jsd that provides the first supporting evidence for this model.

(cont.) Evolutionary analysis indicates that since the X and Y chromosome evolved from a pair of autosomes, retroposition of this gene occurred and was maintained independently in several different mammalian lineages, demonstrating a positive selective pressure for this event. Through targeted disruption of the vertebrate-specific Stra8 gene, we have generated a point of entry into the study of meiotic initiation in mammals. Stra8, which is expressed exclusively in premeiotic germ cells, is required for the initiation of meiosis in mice. In female mice Stra8 is required after the last mitotic division, but prior to meiotic DNA replication. In Stra8-deficient male mice, germ cells arrest at the onset of meiosis, but in a less stringent manner than observed in female germ cells. Additionally, Stra8 appears to be required for proper regulation of spermatogonial stem cells, as Stra8-deficient male mice undergo gradual germ cell depletion, followed by a high frequency of testicular germ cell tumor formation. Gaining a better understanding of these events in the Stra8-deficient mice will provide insight into the regulation of spermatogonial stem cell activity.