The gonadotropin genes: evolution of distinct mechanisms for hormonal control

The glycoprotein hormones (TSH, FSH, LH, CG) are structurally related proteins with diverse physiologic functions. This family of hormones offers an opportunity to address fundamental questions concerning how gene expression is regulated in a cell-specific manner and in response to different hormones. For example, the alpha-subunit gene is expressed in several different pituitary cell types (gonadotropes and thyrotropes) as well as in the placenta. Because it must be coordinantly expressed with the different beta-subunit genes, the alpha-gene provides an interesting model for multihormonal control which varies in a cell-type specific manner. Many of the promoter regulatory DNA sequences and cognate transcription factors in the alpha-gene have been identified. These studies reveal a remarkable series of composite regulatory elements that interact with families of transcription factors that are still being characterized. In contrast, the beta-subunit genes are notable for restricted cell-type expression and more limited hormonal regulation that reflects their individual physiologic roles. The TSH beta gene is expressed only in thyrotropes where, in conjunction with the alpha-gene, it is subject to transcriptional repression by thyroid hormone. The FSH beta gene is expressed in gonadotropes where its expression is controlled primarily by activin and inhibin, with additional regulation by GnRH. The LH beta gene is also expressed in gonadotropes, but it is more dependent upon GnRH input and its expression is unaffected by the activin/inhibin system. The CG beta gene evolved recently from the LH beta gene and in the process, the CG beta promoter acquired new regulatory elements that favor its expression in the placenta rather than the pituitary gland. Less is known about the regulatory elements in the beta genes, in part because highly differentiated cells are required for their normal regulation. This chapter reviews the regulation of this family of genes with an emphasis on recent studies from our laboratory involving the gonadotropins (LH, FSH, CG). Concomitant with our advancing understanding of how the gonadotropin genes are regulated, we are also learning about genetic causes of gonadotropin deficiency syndromes.