Transcriptional Regulation of Early Folliculogenesis

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DESCRIPTION (provided by applicant): Oogenesis is a specialized and regulated process essential for ovarian development, embryogenesis and homeostasis. Pathologic changes in both regulatory and structural components of this pathway affect ovarian differentiation, maintenance, and early embryogenesis. A basic understanding of the biologic modifiers important in oogenesis, especially those, which act on the transcriptional level, would further our understanding of oocyte biology as well as provide insight into pathologic processes including premature ovarian failure, reproductive life span, menopause, ovarian tumors and early embryonic losses. Identification and characterization of genes preferentially expressed in oocytes will be extremely useful in unraveling their oocyte-specific functions and their contribution to ovarian pathology. We utilized in silico subtraction of expressed sequence tags (ESTs) derived from newborn ovary library to discover a novel homeobox gene preferentially expressed in primordial follicles and growing oocytes, which we call Nobox. Nobox is expressed early in folliculogenesis and may play important roles in regulating mammalian oogenesis. To further study the role of Nobox in ovarian development we generated mice homozygous for the Nobox mutant allele using gene targeting by homologous recombination. Ovaries from mice deficient in Nobox can form primordial follicles but fail to grow and by 6 weeks of age are small and lack discernable follicles and oocytes. The histology of these ovaries closely resembles ovaries from women with afollicular type of non-syndromic premature ovarian failure. We propose to study cellular and molecular mechanisms that block follicular development and cause accelerated loss of oocytes in Nobox -/- ovaries. We will characterize NOBOX DNA binding sites and identify genes regulated directly and indirectly by Nobox. We also propose to identify and analyze proteins that interact with NOBOX. These studies will help add to the rapidly increasing amount of information delineating oocyte-specific genetic pathways and to our understanding of the pathologic consequences of mutations in the genes that encode them.