A Family of POU-Domain and Pit-1 Tissue-Specific Transcription Factors in Pituitary and Neuroendocrine Development

Abstract

The anterior pituitary gland provides a model for investigating the molecular basis for the appearance of phenotypically distinct cell types, within an organ, a central question in development. The rat prolactin and growth hormone genes are selectively expressed in distinct cell types (lactotrophs and somatotrophs) of the anterior pituitary gland, which reflect differential mechanisms of gene activation or restriction because of interactions of multiple factors binding to these genes. We find that the pituitary-specific 33,000 dalton transcription factor, Pit-1, normally expressed in somatotrophs, lactotrophs, and thyrotrophs, can bind to and activate both growth hormone and prolactin promoters in vitro at levels even tenfold lower than those normally present in pituitary cells. In the case of the prolactin gene, high levels of expression in transgenic animals required two cis-active regions; a distal enhancer (-1.8 to -1.5 kb) and a proximal region (-422 to +33 bp). Each of these regions alone can direct low levels of fusion gene expression to prolactin-producing cell types in transgenic mice, but a synergistic interaction between these regions is necessary for high levels of expression. The initial appearance of the prolactin transgene expression closely follows the appearance of high levels of Pit-1, but later increases in expression coincident with appearance of mature lactotrophs suggest the operation of additional, critical positive factor(s). Unexpectedly, transgenes containing the distal enhancer removed from its normal context are expressed in both the prolactin-producing lactotrophs and the TSH-producing thyrotrophs, thereby suggesting that sequences flanking this enhancer are necessary to restrict expression to the correct cell type within the pituitary. These data indicate that distinct processes of gene activation and restriction are necessary for the fidelity of cell-type specific expression within an organ. Consistent with this model, we find that lactotroph cell lines that cannot express the growth hormone gene contain high levels of functional Pit-1. We suggest a large, highly related POU-domain gene family, potentially exceeding 100 members, has been conserved and expanded in evolution to meet the increasing requirements for more intricate patterns of cell phenotypes. The POU-domain subgroup of the homeodomain gene family, in concert with other homeodomain proteins and with other classes of transcription factors, is likely to contribute to the establishment of the mammalian neuroendocrine system.

A Case of Acquired Deficiency of Pituitary GH, PRL and TSH, Associated with Type 1 Diabetes Mellitus

“…Both cases had heterozygous C-T substitutions in the Pit-1 gene, which resulted in a proline to leucine substitution. Two mutations resulted at different positions, one at codon 14 and the other at codon 24, but both mutations in the two patients were located in the same, highly conserved region of the main transactivation domain in Pit-1 [20]. Disruption of the predicted major transactivation domain by the amino acid substitution severely compromises transactivation of Pit-1 target genes.…”

Appearance of the pituitary factor Pit-1 increases chromatin remodeling at hypersensitive site III in the human GH locus

“…The POU homeodomain is responsible for low-affinity, non-specific DNA binding (Ingraham et al 1990b), and for protein-protein interactions (Bradford et al 2000). The N-terminal trans-activation domain has been shown previously to be responsible for transcriptional activation (Ingraham et al 1990a), and it is thus intriguing that this region might not be required for RNA pol II activity in the GH LCR, but is required for chromatin modifications. Thus, in addition to transcriptional activation, the N-terminal domain may contribute to the recruitment of factors, such as histone acetyltransferases, which modify chromatin.…”

Changes in expression of the prolactin and growth hormone gene during different reproductive stages in the pituitary gland of turkeys

“…Transcriptional regulators of avian PRL have not been studied in detail. In mammals the transcription factor Pit-I/GHF-1 regulates both PRL and GH genes (Ingraham et al, 1990). Wong et al (1992b) recently cloned the turkey counterpart of the mammalian Pit-1/GHF-1.…”