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<p>A unique feature of the fetal gonad is its ability to form two distinct organs,
the testis and the ovary, from a single bipotential primordium. The outcome of this
decision, which is made by a population of somatic cells known as the bipotential
supporting cell precursors, determines whether an embryo will develop as a phenotypic
male or female. Though several molecular pathways have been shown to be required for
female fate determination in vertebrates, the intricacies of ovarian morphogenesis
are not well understood. A key event in ovarian development occurs around birth, when
meiotic germ cells and somatic granulosa cells organize into primordial follicles,
the structures that generate mature oocytes for ovulation in adult females. We investigated
the embryonic origins and proliferative properties of granulosa cells in the fetal
mouse ovary and found that the precursors emerge from the ovarian surface epithelium
and then enter mitotic arrest in a specification process that extends from the bipotential
stage to the end of the postnatal follicle assembly period. Maintenance of cell cycle
arrest in granulosa cell precursors appears to be regulated by Wnt signaling. The
first granulosa cells to be specified were exclusively incorporated into the subset
of follicles that begin to grow immediately upon assembly. We show that this first
group of granulosa progenitors derives from the supporting cell precursors present
in the bipotential gonad. Interestingly, both XX and XY supporting cell precursors
were mitotically arrested towards the end of the bipotential period, indicating that
adoption of supporting cell fate might be regulated by the cell cycle. We also show
that antagonism of Notch signaling may be required for these precursor cells to exit
the cell cycle and differentiate.</p><p>In Witschi's classic model of vertebrate gonad
development, the cortex and medulla of the undifferentiated gonad expand and differentiate
in a mutually exclusive manner to yield the mature ovary and testis (Witschi 1951).
Estrogen acts on both the cortex and medulla to promote female fate determination
and ovary development in non-mammalian vertebrates. However, the downstream receptors
and targets through which estrogen exerts its effects on the gonad have not yet been
elucidated. We selected the red-eared slider turtle Trachemys scripta as a model with
which to address this question. We first characterized the cellular composition of
the turtle gonad before and after sex determination, identifying four populations
of somatic cells distinguishable by their location within the gonad as well as the
complement of transcription factors expressed. This information was then applied to
an investigation of estrogen signaling pathways in the turtle ovary. We show that
i) estrogen likely acts through its canonical receptors rather than a non-canonical
pathway involving ERK signaling; ii) early exposure to estrogen resulted in the premature
downregulation of a testis-specific gene, SOX9, in the medulla; iii) less estrogen
is needed to promote ovarian differentiation in the cortex of the gonad than to repress
testicular differentiation of the medulla, consistent with the localized production
of estrogen in the medulla; and iv) estrogen's repressive effect on SOX9 expression
may be mediated by Wnt signaling. </p><p>Our findings add complexity to the standard
model of how the male and female supporting cell lineages are established in mice,
reveal evolutionary conservation between mice and turtles in the timing of granulosa
cell specification relative to sex determination., and refine our understanding of
how estrogen acts to promote ovarian development in non-mammalian species.</p>
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