OVARIAN PRIMORDIAL FOLLICLE
DEVELOPMENT
The proposed research is directed toward developing a
better understanding of the mechanisms that control
primordial follicle development. This process is
essential for the establishment and maintenance of female
reproduction. Primordial follicle development involves
the initial event of primordial follicle assembly and the
subsequent event of primordial to primary follicle
transition. The process involved in primordial follicle
assembly is distinct from that of primordial to primary
follicle transition and both will be investigated in the
proposed research. The manner by which locally produced
ovarian substances and hormones regulate these processes
are of particular interest. Emphasis is placed on the
elucidation of cell-cell interactions between precursor
theca cells, granulosa cells and the oocyte. Previous
research and preliminary studies have demonstrated that
the control of primordial follicle development and
subsequent folliculogenesis appears to be mediated by the
local production and action of specific paracrine factors
involving theca cells, granulosa cells, and the oocyte.
Preliminary studies have shown that steroid hormones
(i.e. estrogen and progesterone) play a critical role in
the onset of primordial follicle assembly. Preliminary
studies also demonstrate that primordial to primary
follicle transition requires integrated interactions
between the oocyte, granulosa cells and precursor theca
cells involving kit ligand (KL), basic fibroblast growth
factor (bFGF), leukemia inhibitory factor (LIF),
keratinocyte growth factor (KGF) and bone morphogenic
protein-4 (BMP4). "THE GENERAL HYPOTHESIS TESTED
IS THAT HORMONES INFLUENCE THE PARACRINE GROWTH FACTOR
MEDIATED INTERACTIONS BETWEEN THE OVARIAN SOMATIC CELLS
AND THE OOCYTE TO CONTROL PRIMORDIAL FOLLICLE ASSEMBLY
AND DEVELOPMENT". More defined sub-hypotheses
are presented for each specific aim below. Interactions
between hormones and paracrine growth factors provide an
efficient mechanism to control primordial follicle
development. It is anticipated that abnormalities in
these cellular interactions will influence female
fertility, menopause onset and promote pathophysiologies
such as premature ovarian failure. The experimental
approach consists of the following specific aims: 1)
Elucidate the hormonal and paracrine growth factor
control of primordial follicle assembly. 2) Elucidate the
hormonal and growth factor control of the primordial to
primary follicle transition. 3) Elucidate the
physiological importance of specific factors that mediate
primordial follicle development. Completion of these
specific aims will extend previous observations and
provide insight into the role of growth factor mediated
cell-cell interactions in regulating primordial follicle
development. The critical developmental periods to be
examined include the induction of primordial follicle
assembly and the primordial to primary follicle
transition. It is anticipated that the specific cell-cell
interactions will change between these developmental
periods. The differential effects of hormones on growth
factors and relevant receptors have a critical role in
later stages of follicle development, but remain to be
determined in primordial follicle development.
Observations are anticipated to provide insight into the
molecular and cellular control of primordial follicle
development. The information obtained will be used to
understand the onset of puberty and menopause, as well as
provide insight into the potential future design of
diagnostic procedures and therapeutic treatments for
abnormal ovarian conditions such as premature ovarian
failure (POF) and forms of female infertility. An example
of a future experiment proposed is to determine if
mutation(s) exist in any of the repertoire of growth
factors and/or receptors established in the current study
as potential causal factors for disease states such as
premature ovarian failure.