Ontogeny of the oestrogen receptors ESR1 and ESR2 during gonadal development in the tammar wallaby, Macropus eugenii

Abstract

Oestrogen has wide ranging effects in development mediated mainly via the two oestrogen receptors, a (ESR1, also known as ERa) and b (ESR2, also known as ERb). Oestrogen is the key factor that directs the indifferent gonad to become an ovary in many non-mammalian vertebrates. Oestrogen is not required for early ovarian differentiation in mammals but can disrupt normal testicular development in eutherians. Surprisingly, exogenous oestrogen can cause sex reversal of an XY gonad in two marsupials, the North American opossum and the tammar wallaby. To understand the mechanism by which oestrogen induces sex reversal, we characterised the genes for ESR1 and ESR2 and examined their expression during gonadal differentiation in the tammar wallaby, Macropus eugenii. Both receptors were expressed in the somatic cells and germ cells of the indifferent gonad in both XX and XY foetuses throughout all stages of development, and persisted in these cells into adulthood. ERs were also present in many other tissues including kidney, pituitary and mammary gland. ER mRNA was not significantly altered by exogenous oestrogen in cultured XY gonads but the receptors translocated to the nucleus in its presence. These findings confirm that there is conserved expression of the ERs in the indifferent gonad despite the lack of available ligand during early gonadal development. The receptors can respond to exogenous estrogen at this early stage and are capable of transducing signals in the early mammalian gonad. However, the selective forces that maintained conserved ER expression in this tissue remain unknown.

Assessing the Ability of Developmentally Precocious Estrogen Signaling to Recapitulate Ovarian Transcriptomes and Follicle Dynamics in Alligators from a Contaminated Lake

“…Limited evidence exists describing primordial germ cell (PGC) behavior in the alligator, but work by Smith and Joss (1993) has indicated the presence of PGCs in the cortex of the undifferentiated gonad as early as Stage 20, one stage after experimental estrogen dosing in the present study. Furthermore, ERs are actively expressed in the early gonad in alligators (described herein and in Rice et al 2017), birds (Andrews et al 1997;Ge et al 2012;Guioli and Lovell-Badge 2007), turtle (Bergeron et al 1998;Crews 2007, 2009), eutherian mammals (La Sala et al 2010), and marsupials (Calatayud et al 2010), and mammalian data supports receptor expression by PGCs themselves (Calatayud et al 2010;La Sala et al 2010). This would collectively suggest that PGCs are present in the gonad during precocious E 2 treatment and are capable of responding to receptor activation.…”

Oestrogen blocks the nuclear entry of SOX9 in the developing gonad of a marsupial mammal

“…A total of 12 male fetuses were collected at day 25 of gestation, and pairs of gonads were isolated and placed, one into control media and the other into oestrogen media. Gonads were cultured for 5 days (120 hr) as previously described [12], with either Dulbecco's modified Eagle medium (DMEM)/10% fetal calf serum (FCS)/50 mg/ml ampicillin (control) or with the addition of estradiol benzoate (to a final concentration of 100 ng/ml). This dose was chosen to ensure sufficient oestrogen penetration into the cultured gonad.…”

“…A genetically controlled sex determination mechanism may have evolved in mammals to protect the young developing in utero from the effect of large quantities of oestrogen in the fetoplacental unit [8,9]. However, oestrogen receptor expression is maintained in the indifferent mammalian gonad [10,11] despite their apparent lack of function, and exposure of gonads to exogenous oestrogen activates the translocation of the receptors to the nuclei of indifferent gonadal cells [12]. Not surprisingly, the mammalian placenta is highly effective in metabolizing hormones before they reach the developing fetus [13], protecting it from maternal influences.…”

“…The effects of oestrogen are mediated through the oestrogen receptors (ERs) in the gonad [2]. Treatment of the tammar XY gonads at day 25 of gestation with oestrogen in culture causes the oestrogen receptors to move from a cytoplasmic to nuclear localization within the cell, consistent with their activation and ability to affect gene transcription in an oestrogen-dependent manner [12]. The nuclear translocation of both receptor proteins in the presence of exogenous oestrogen in culture confirms the ability of the receptors to respond functionally to the ligand, even at early developmental stages [12].…”

State of the Art of Therapeutic Endocrinology

“…Despite the highly conserved role of oestrogen in nonmammalian vertebrates, its function in the development of the mammalian ovary remains less clear. Interestingly, expression of the oestrogen receptors, which mediate oestrogen actions within the cell, is maintained in the somatic cells of the indifferent gonads of mice, humans, goats, sheep and marsupials indicative of a highly conserved role for oestrogen in the early mammalian gonad (Calatayud et al 2010). It was a surprising finding then, that oestrogen was not required for initial ovarian development in mice (Couse and Korach 1999).…”