Regulation of the follicle-stimulating hormone beta gene by the LHX3 LIM-homeodomain transcription factor.

FSH is a critical hormone regulator of gonadal function that is secreted from the pituitary gonadotrope cell. Human patients and animal models with mutations in the LHX3 LIM-homeodomain transcription factor gene exhibit complex endocrine diseases, including reproductive disorders with loss of FSH. We demonstrate that in both heterologous and pituitary gonadotrope cells, specific LHX3 isoforms activate the FSH beta-subunit promoter, but not the proximal LHbeta promoter. The related LHX4 mammalian transcription factor can also induce FSHbeta promoter transcription, but the homologous Drosophila protein LIM3 cannot. The actions of LHX3 are specifically blocked by a dominant negative LHX3 protein containing a Kruppel-associated box domain. Six LHX3-binding sites were characterized within the FSHbeta promoter, including three within a proximal region that also mediates gene regulation by other transcription factors and activin. Mutations of the proximal binding sites demonstrate their importance for LHX3 induction of the FSHbeta promoter and basal promoter activity in gonadotrope cells. Using quantitative methods, we show that the responses of the FSHbeta promoter to activin do not require induction of the LHX3 gene. By comparative genomics using the human FSHbeta promoter, we demonstrate structural and functional conservation of promoter induction by LHX3. We conclude that the LHX3 LIM homeodomain transcription factor is involved in activation of the FSH beta-subunit gene in the pituitary gonadotrope cell.

Transcriptional control during mammalian anterior pituitary development.

The mammalian anterior pituitary gland is a compound endocrine organ that regulates reproductive development and fitness, growth, metabolic homeostasis, the response to stress, and lactation, by actions on target organs such as the gonads, the liver, the thyroid, the adrenals, and the mammary gland. The protein and peptide hormones that control these physiological parameters are secreted by specialized pituitary cell types that derive from a common origin in the early ectoderm. Collectively, the broad physiological importance of the pituitary gland, its intriguing organogenesis, and the clinical and agricultural significance of its actions, have established pituitary development as an excellent model system for the study of the gene-regulatory cascades that guide vertebrate cell determination and differentiation. We review the transcriptional pathways that regulate the commitment of the individual pituitary cell lineages and that subsequently modulate trophic hormone gene activity in the differentiated cells of the mature gland.