Academic journal article Genetics

Genomewide Discovery and Classification of Candidate Ovarian Fertility Genes in the Mouse

Academic journal article Genetics

Genomewide Discovery and Classification of Candidate Ovarian Fertility Genes in the Mouse

Article excerpt

ABSTRACT

Female infertility syndromes are among the most prevalent chronic health disorders in women, but their genetic basis remains unknown because of uncertainty regarding the number and identity of ovarian factors controlling the assembly, preservation, and maturation of ovarian follicles. To systematically discover ovarian fertility genes en masse, we employed a mouse model (Foxo3) in which follicles are assembled normally but then undergo synchronous activation. We developed a microarray-based approach for the systematic discovery of tissue-specific genes and, by applying it to Foxo3 ovaries and other samples, defined a surprisingly large set of ovarian factors (n=348, ~1% of the mouse genome). This set included the vast majority of known ovarian factors, 44% of which when mutated produce female sterility phenotypes, but most were novel. Comparative profiling of other tissues, including microdissected oocytes and somatic cells, revealed distinct gene classes and provided new insights into oogenesis and ovarian function, demonstrating the utility of our approach for tissue-specific gene discovery. This study will thus facilitate comprehensive analyses of follicle development, ovarian function, and female infertility.

DISORDERS of female infertility and early menopause due to depletion of ovarian follicles, such as premature ovarian failure, are among themostcommon chronic medical conditions affecting women. the incidence of female infertility in the united states is ~13%, and ovarian dysfunction is the mostcommon underlying cause (KUMAR et al. 2007). Premature ovarian failure (menopause prior to the age of 40) has multiple systemic consequences due to sex steroid deficiency (such as osteoporosis) and affects 1%of women (KALANTARIDOU and NELSON 2000). Substantial progress has recently been made in studies of male infertility, as exemplified by the discovery of Y chromosome microdeletions resulting in azoospermia (PRYOR et al. 1997), but common causes of female infertility syndromes remain elusive. Although rare metabolic and genetic causes of female infertility are known, such as galactosemia (KAUFMAN et al. 1979) or mutations in the follicle stimulating hormone receptor (AITTOMAKI et al. 1995), the etiologies of female infertility syndromes including primary amenorrhea, premature ovarian failure, and polycystic ovarian disease are largely unknown. These disorders, however, are believed to have an ovarian basis with a major hereditary component (KUMAR et al. 2007).

Female infertility likely results from defects at various stages of follicle assembly and development. In mammals, the postnatal period (birth to 2 weeks in the mouse) is an active phase of ovarian development when primordial follicles (PFs) are formed and the first wave of follicle activation begins at around postnatal day (PND) 3. Individual PFs remain quiescent until they resume growth via a poorly understood process known as PF activation (PFA). PFA begins immediately after follicle assembly is complete at PND3 and continues until follicle depletion at menopause. Because all activated follicles ultimately undergo ovulation or atresia, PFA represents an irreversible commitment to follicle growth (MCGEE and HSUEH 2000). Thus, in the normal premenopausal ovary, the vast majority of follicles are primordial and quiescent (Figure 1C), and the small percentage of follicles that are actively growing do so in an asynchronous manner. Furthermore, large preovulatory follicles comprise a disproportionate share of the ovarian mass. These aspects of ovarian physiology have presented major hurdles to the identification and study of factors that function during early follicle growth.

The forkhead transcription factor Foxo3 is a master regulator of PFA (CASTRILLON ET AL. 2003; HOSAKA et al. 2004). PF assembly is normal in female mice bearing a null Foxo3 mutation (JOHN et al. 2007). Immediately thereafter, however, PFs undergo global activation and grow in an essentially synchronized manner, resulting in ovarian hyperplasia by PND14. …

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