Early ovarian follicle dysgenesis in a disintegrin and metalloproteinase with thrombospondin motifs type 1 (ADAMTS-1) null mice

Abstract

<jats:p>

ADAMTS-1 is a multi-domain, multi-functional matrix metalloproteinase expressed in the mouse ovary during folliculogenesis and ovulation. Adult ADAMTS-1 null female mice are infertile; however, the exact mechanism responsible for their reproductive failure is yet to be explained. ADAMTS-1 null ovaries prior to and following ovulation were examined and a defect in ovarian follicle development was identified. A classification system was devised and used to identify morphological differences between normal and ADAMTS-1 null ovaries. The phenotype indicated a progressive loss of follicle structural integrity ranging from a slight loss of shape, to full structural dysgenesis. As a result, large numbers of oocytes with healthy appearance were found with no surrounding follicle structure. The numbers of preantral follicles was not altered, but type 6 (early antral) follicles in the ADAMTS-1 null ovaries were significantly reduced (P &lt; 0.05) when compared to wild-type ovaries suggesting initiation of follicular degeneration coincident with antrum formation. There was also a significant decrease (P &lt; 0.05) in the number of periovulatory follicles (type 7 and 8) in the ADAMTS-1 null ovaries. This suggests that late folliculogenesis, in the period of rapid growth and expansion is disrupted when ADAMTS-1 is not present and results in fewer follicles available for ovulation. Further, we have demonstrated that the active form of ADAMTS-1 is present in the thecal-granulosa boundary of the ovarian follicle suggesting a role in extracellular matrix remodeling at this boundary during follicle growth. Analyses of the basement membrane at this boundary both in growing and ovulating follicles indicate that ECM remodeling in this region is indeed disrupted. These data demonstrate that remodeling of surrounding structural matrix is crucial to follicle growth and structural integrity. Functional ADAMTS-1 is important for matrix remodeling during the growth of the follicle, particularly during antrum formation. </jats:p>