are interested in how the brain controls reproduction through the
neuroendocrine system with emphases on development, hormone signaling, gene
expression, circadian rhythm, and mouse models of human disease.
|Hormone Action in the Pituitary|
testosterone, and progesterone regulate pituitary luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) in concert with pulsatile GnRH from the
hypothalamus and autocrine activin and other growth factors. The interactions
of these signaling cascades produce differential regulation of the synthesis
and secretion of LH versus FSH from the gonadotrope cell of the pituitary
leading to fertility, the estrous cycle, puberty, and menopause. We utilize in
vitro, cell culture, and in vivo genetic mouse models to understand the
integration and interactions of these signaling cascades.
|GnRH Neuron Development|
The GnRH neurons are born in the olfactory placode
at e11 in the mouse, only 800 cells total. They migrate up to the olfactory
bulb and back down to the hypothalamus. Defective migration or the accompanying
differentiation of GnRH neurons is a cause of human infertility. We study both mouse and cell culture models of
differentiation and migration, elucidating roles for homeodomain proteins,
neuropeptides and their receptors, chromatin modifications, and transcriptional
co-repressors and co-activators and determining their mechanisms of action.
||Pituitary Cell Fate|
Cell fate of the gonadotrope within the pituitary is determined by internal genetic programs coupled with external cues. We study both mouse and cell culture models of differentiation and migration, elucidating roles for homeodomain proteins, neuropeptides and their receptors, chromatin modifications, and transcriptional co-repressors and co-activators and determining their mechanisms of action.
||Circadian Rhythms in Reproduction|
of circadian rhythm genes leads to profound infertility, absent puberty and
estrous cycles, and lack of pulsatile GnRH secretion. Studying the actions of
the “clock” genes in an immortalized hypothalamic neuron that secretes GnRH in
the physiological pulsatile pattern, along with reproductive function in
genetically modified mice, will reveal the molecular mechanisms for specifying
the rhythms of the reproductive cycle and pulsatile depolarization of the
hypothalamic neurons. Steroid hormone feedback contributes to these rhythms and
regulates the estrous cycle, puberty, and reproductive senescence. Thus,
studies with targeted knock-out of nuclear receptors and clock genes in mice
coupled with studies of cells in vitro can reveal the underlying mechanisms of