PLACENTAL GROWTH HORMONE AHD RELATED PROTEINS

Abstract

The human growth hormone (hGH) gene cluster contains the pituitary hGH-H gene as well as 4 placentally expressed genes: hCS-A, hCS-B, hCS-L, and hGH-V (placental GH). The 4 placental genes are coordinately induced during fetal development. There is a developmentally regulated switch in the relative expression of hCS-A and hCS-B. The hGB-V gene produces a maternally circulating hormone that reaches maximal levels during the 2nd and 3rd trimesters, as well as a larger protein, hGH-V2, that remains associated with the cell. hGH-V maintains the full spectrum of GH-like bioactivity but is 7-fold more purely somatogenic than hGB-N. The hCS-L gene has lost its normal exon 2 splice donor and undergoes extensive alternative splicing. Expression of the growth hormone receptor (GHR) has been detected in all 4 layers of the placenta, suggesting a means of signal transduction for the placental GH isoforms. The placental villi selectively express an alternatively spliced form of the receptor lacking exon 3, hGHRd3, while decidua and chorion predominantly express the full-length receptor. Both forms of hGH receptor possess indistinguishable ligand binding activities when expressed in Xenopus oocytes. To study the developmental and tissue-specific regulation of this gene cluster, 150 kb of DHA including and flanking the cluster have been analyzed for DHase I hypersensitive sites (HSS). A set of HSS were identified in syncytiotrophoblastic nuclei and in the nuclei of a GH-secreting pituitary adenoma about 40 kb upstream and >20 kb downstream of the cluster. These sites were absent from a number of cell types that do not express the GH-related genes. Constructs containing the hGH-N gene plus and minus the HSS were used to generate transgenic mice. When linked to the 5′ -HSS the hGH-N gene was specifically expressed in the pituitary with serum levels of 2-10 ng/ml hGH-H. The 5′-HSS reformed in the transgene in nuclei from pituitaries of transgenic mice. The possibility that this region, remote from the structural genes, is critical to their activation in transgenic mice suggests a novel mechanism for the control of the members of this cluster.