The anterior pituitary synthesizes hormones that control reproduction, homeostasis, growth, stress response, and lactation. Since each of these physiological responses must be regulated independently, individual pituitary endocrine cell types are specialized to produce distinct hormones. During development, each cell lineage arises in a unique spatial and temporal pattern. The gonadotrope, which regulates reproductive function through the synthesis of the gonadotropins Luteinizing Hormone (LH) and Follicle- Stimulating Hormone (FSH), arises last in this process, as defined by the appearance of the beta subunits of its hallmark proteins. However, its emergence can be traced throughout pituitary development by the sequential appearance of earlier markers of the lineage, first the alpha subunit shared by LH, FSH and Thyroid-Stimulating Hormone, followed by the orphan nuclear receptor Steroidogenic Factor 1, then Gonadotropin-Releasing Hormone Receptor, and finally the LH beta and FSH beta subunits. Using targeted tumorigenesis in transgenic mice, we have developed immortalized cell lines that represent sequential developmental stages of the gonadotrope lineage and the closely related thyrotrope. Utilizing these novel cell models coupled with genetic manipulation in vivo, we propose to elucidate the program of regulators involved in the progression of differentiation to the mature gonadotrope. In the first three aims, we will focus on three select classes of regulatory factors, GATA-binding proteins, basic helix-loop-helix proteins, and LIM-homeodomain proteins. Members of each family are known to directly regulate gonadotropin subunit genes and to be involved in specification of pituitary lineages; however, the balance, interplay, and timing of their actions and those of their co-factors remain to be delineated. These DNA- binding proteins and their associated co-regulators are themselves regulated during lineage progression. Our hypothesis is that programs of closely related factors and their associated co-regulators sequentially occupy control elements in gonadotrope target genes to determine lineage progression and maturation. In the fourth aim, we will take an unbiased approach to defining the mature gonadotrope phenotype at the molecular level, utilizing innovative bioinformatic and molecular methods to identify key components of the gonadotrope differentiation program. ? ? ?
Showing the most recent 10 out of 62 publications
