Postnatal Sex Reversal of the Ovaries in Mice Lacking Estrogen Receptors α and β

Couse, John F.; Hewitt, Sylvia C.; Bunch, Donna O.; Sar, Madhabananda; Walker, Vickie R.; Davis, Brandon; Korach, Kenneth S.

doi:10.1126/science.286.5448.2328

Cited by 533 publications

(334 citation statements)

References 33 publications

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“…Neither deletion of the aromatase gene (ArKO) [11] nor mutations of the aromatase protein [12] affect ovarian formation. Although in these cases maternal estrogens could compensate for the lack of local estradiol synthesis, estrogen receptor α and β (ERα and β or Esr1 and Esr2) knockout mice show no defects on fetal ovarian development [13], suggesting that, at least in mice, estrogens do not participate in this process.…”

Section: Fetal Ovariesmentioning

confidence: 99%

“…In immature ERα and ERβknockout mice, LH levels are elevated [13]. The high levels of LH result in a premature maturation of the ovary characterized by the presence of adult-like follicles in prepubertal females [13].…”

Section: Neonatal Ovariesmentioning

confidence: 99%

“…The high levels of LH result in a premature maturation of the ovary characterized by the presence of adult-like follicles in prepubertal females [13]. Indirectly, this result suggests that, in prepubertal animals, ovarian estradiol contributes to maintain normal levels of gonadotropins via its well-known regulatory feed-back in the pituitary gland.…”

Section: Neonatal Ovariesmentioning

confidence: 99%

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Aromatase expression in the ovary: Hormonal and molecular regulation

2008

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Summary-Estrogens are synthesized by the aromatase enzyme encoded by the Cyp19a1 gene, which contains an unusually large regulatory region. In most mammals, aromatase expression is under the control of two distinct promoters a gonad-and a brain-specific promoter. In humans, this gene contains 10 tissue-specific promoters that are alternatively used in various cell types and tumors. Each promoter is regulated by a distinct set of regulatory sequences and transcription factors that bind to these specific sequences. The cAMP/PKA/CREB pathway is considered to be the primary signaling cascade through which the gonad Cyp19 promoter is regulated. Very interestingly, in rat luteal cells, the proximal promoter is not controlled in a cAMP dependent manner. Strikingly, these cells express aromatase at high levels similar to those found in preovulatory follicles, suggesting that alternative and powerful mechanisms control aromatase expression in luteal cells and that the rat corpus luteum represents an important paradigm for understanding alternative controls of the aromatase gene. Here, the molecular and cellular mechanisms controlling the expression of the aromatase gene in granulosa and luteal cells are discussed.

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Section: Fetal Ovariesmentioning

confidence: 99%

Section: Neonatal Ovariesmentioning

confidence: 99%

Section: Neonatal Ovariesmentioning

confidence: 99%

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Aromatase expression in the ovary: Hormonal and molecular regulation

2008

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“…This is in keeping with the fact that Foxl2 overexpression in XY Sertoli cells in transgenic mice leads to seminiferous tubule disorganization and to the development of ovotestis-like gonads. [26] Sertoli-like cells expressing Sox9 in postnatal ovaries appear in XX mice double mutant for the estrogen receptor genes (Esr1/Esr2 [33]). This, and the fact that FOX factors are able to interact with ESRs, [34] prompted the authors to study a potential interaction between Esr (or ER) and Foxl2 in the repression of TESCO.…”

Section: Pr Ospects and Overviews R A Veitiamentioning

confidence: 99%

FOXL2 versus SOX9: A lifelong “battle of the sexes”

Veitia

2010

BioEssays

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Testis determination in most mammals is regulated by a genetic hierarchy initiated by the SRY gene. Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY. Recent studies challenge this view and show that the ovary constantly represses male-specific genes, from embryonic stages to adulthood. Notably, the absence of the crucial ovarian transcription factor FOXL2 (alone or in combination with other factors) induces a derepression of male-specific genes during development, postnatally and, even more interestingly, during adulthood. Strikingly, in the adult, targeted ablation of Foxl2 leads to a molecular transdifferentiation of the supporting cells of the ovary, which acquire cytological and transcriptomic characteristics of the supporting cells of the testes. These studies bring many answers to the field of gonadal determination, differentiation and maintenance, but also open many questions. Keywords:.F OXL2; ovary determination; ovarian maintenance IntroductionGonadal sex determination is a process that implies a unique decision to make a testis or an ovary out of a bipotential primordium. In most mammals, sex determination is equated with testis determination, whereas ovarian determination has been considered a default process. That is, absence of the testisdetermining factor would automatically lead to the development of an ovary (in appropriate conditions). Recent articles challenge this view and show that in the ovary active mechanisms are required to maintain the differentiated state. [1,2] The bipotential gonad is made up of four presumptive cell lineages: germ cells (which have an extraembryonic origin) and three types of somatic cells. The somatic component involves the supporting cell precursors, which will give rise to Sertoli cells in the male or granulosa cells in the female, the steroidogenic precursors, which differentiate into Leydig cells (male) and theca cells (female), and finally the connective tissue cells yielding other important structures. [3] From a genetic perspective, the SRY gene is pivotal in switching on the testis-determining cascade.[4] Indeed, murine Sry transcripts appear in the presumptive Sertoli cells from 10.5 days postcoitum and for about 2 days, at the right moment for testis determination. [5] In other mammals, including man, SRY is expressed from the period of testis determination until adulthood [6]). It seems now that the main task of Sry/SRY is to directly activate the gene Sox9, which also encodes a transcription factor. Recently a gonad-specific enhancer that mediates testis Sox9 expression, called TESCO, has been identified. [7] Indeed, Sry along with the steroidogenic factor 1 (Sf1) binds to multiple elements within the TESCO. Moreover, mutation, co-transfection, and sex-reversal studies suggest the existence of a positive feedback circuit. First, Sf1 and Sry cooperatively up-regulate Sox9 transcription. Then, Sox9 and Sf1 recognize the enhancer to maintain the expression of the former in the absence of Sr...

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“…ERbKO mice exhibit less abnormalities, which are also seen in ERaKO mice (Krege et al 1998). The normal maintenance of germ and somatic cells in the postnatal ovary was severely affected, with follicle transdifferation into a testis-like tissue in the ERa/ERb double KO (knockout) mice (Couse et al 1999). However, these single and double KO mice manage to survive to adulthood, albeit with retarded growth (Korach 1994;Eddy et al 1996;Krege et al 1998;Couse et al 1999).…”

Section: Physiological Roles Of Era and Erb -Er Ko Micementioning

confidence: 99%

Molecular mechanism of a cross‐talk between oestrogen and growth factor signalling pathways

et al. 2000

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Oestrogen (E 2 ) plays signi®cant roles in variety of biological events such as the development and maintenance of female reproductive organs, bone and lipid metabolisms. More recently, from study of knock-out mice de®cient in oestrogen receptor (ER) a and ERb it turned out that normal spermatogenesis requires the E 2 actions. Furthermore, this female steroid hormone is also well known to be deeply involved in many pathophysiological events such as osteoporosis and cancer development in female reproductive organs. It is particularly well known that most breast cancer is dependent on E 2 in its development. Such E 2 actions are thought to be mediated through two subtypes of ERs. Growth factors have been shown to synergize in this E 2 signalling pathway, although the actual molecular mechanism largely remains unknown.Recently, we found that the MAP kinase activated by growth factors phosphorylates the Ser 118 residue of the human ERa A/B domain and this phosphorylation potentiates the N-terminal transactivation function (AF-1) of human ERa, indicating the possible molecular mechanism of a novel cross-talk between E 2 and growth factor signalling pathways. More recently, we have identi®ed a coactivator associating with the hERa AF-1 in a MAPK-mediated phosphorylationdependent manner. In this review, the molecular mechanism of this cross-talk is discussed in terms of the transactivation function of ERs, and their coactivators.

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Postnatal Sex Reversal of the Ovaries in Mice Lacking Estrogen Receptors α and β

Cited by 533 publications

References 33 publications

Aromatase expression in the ovary: Hormonal and molecular regulation

Aromatase expression in the ovary: Hormonal and molecular regulation

FOXL2 versus SOX9: A lifelong “battle of the sexes”

Molecular mechanism of a cross‐talk between oestrogen and growth factor signalling pathways

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