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RESEARCH:
SUMMARY
We
are identified as male or female at birth and it is this distinction
that determines how we are raised, how we view the world, and
how the world views us. The genitourinary tract is the organ
system most commonly affected by birth defects, and some of
these are increasing in frequency. For example, the frequency
of intersex births range from 1 in 2,000 to 1 in 4,500, making
it roughly as common as being born with cystic fibrosis. This
suggests the pathway that the bipotential gonad takes to develop
into an ovary or testis may be prone to errors. Even if the
fetus is born appearing anatomically normal, gene expression
mistakes that are made during development can also contribute
to serious problems that remain latent until later in life when
the addition of hormones can wreak havoc on a fragile system.
These conditions can include serious health issues such as infertility
or worse, gonadal cancer.
The
Jorgensen Laboratory is interested in how the gonads are formed
and the regulatory decisions that contribute to decisions of
a testis or ovarian fate. We use cell and molecular biology
tools to recognize genes that are expressed specifically in
the male or female gonad during sex differentiation. We then
combine these techniques with the use of genetically altered
mouse models to characterize the functional significance and
regulation of these factors. In the end, we assess our findings
in the context of real health issues including gonadal birth
defects, infertility, and gonadal cancers.
IRX3
IS A FEMALE-SPECIFIC FACTOR
We
identified Irx3 as a female specific gene with the use of a
gene expression array comparing male and female gonads during
sex differentiation. Irx3 is a factor that is conserved in species
ranging from yeast to man and has known roles in spatial organization
of early embryos and determines the fate of the ventral spinal
cord in late development of mammalian species. Its role in gonad
development, however, is unknown. We found that the Irx3 signal
persists in germ cell-depleted XX gonads resulting from busulfan
treatment, suggesting that germ cells are not required for Irx3
expression. In addition, we confirmed that somatic cells were
the source of IRX3 expression by co-localizing its signal with
a somatic cell marker, GATA4. The expression profile of Irx3
corresponds to milestones in female gonad development. The initial
increase in its expression coincides with the onset of germline
cyst formation and the transition of primordial germ cells from
mitotic proliferation to meiotic division. Irx3 persists through
development and then abruptly decreases just after birth. This
decline overlaps with timing of programmed germline cyst breakdown
that results from the invasion of somatic cells in between neighboring
germ cells and the formation of primordial follicles. In contrast,
male gonads express 50% Irx3 message relative to females initially
and expression declines further over time.
We
are currently developing and using a variety of genetically
modified mouse models to understand the functional significance
of Irx3 in ovarian development. We have evidence from these
mice to suggest that Irx3 is essential for normal ovarian development
and oocyte maturation. We are also using gonad tissue to characterize
the Irx3 promoter to learn more about its regulation. Finally,
we are utilizing chromatin immunoprecipitation studies to identify
its downstream targets.
SEX-SPECIFIC
REGULATION OF SF1 DURING GONAD DEVELOPMENT
On
the one hand, the roles that Sf1 plays in endocrine function
and gonad development have been widely characterized. Indeed,
human patients with mutations in SF1 are sex-reversed, lack
normal gonad structure, and suffer from severe adrenal insufficiency.
The spatial and temporal cues that differentiate Sf1 expression
in male and female gonads, however, remain a mystery and we
are pursuing studies to understand Sf1 regulation in embryonic
Sertoli, Leydig, and pre-granulosa cells in the context of the
developing gonad itself. Initially, Sf1 is expressed similarly
in male and female gonads; however, shortly after sex determination,
Sf1 expression diminishes in the female gonad, only to return
just before birth. We are currently characterizing 2 distinct
regions of the proximal Sf1 promoter that exhibit female gonad-specific
regulation based on transient transfection assays performed
in embryonic gonad explants. In addition, we are examining the
molecular mechanism behind hedgehog signaling and maintenance
of Sf1 expression in Sertoli cells of the male gonad.
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