In mammalian development, cell specification and organogenesis are achieved by the regulated expression and repression of specific subsets of genes. The anterior pituitary gland, comprised of five cell types that arise from a common precursor, is an excellent model system for understanding these developmental processes. Examination of factors regulating transcription of cell-specific genes leads to a better understanding of how cells differentiate from one another. One of the major goals of this thesis work is investigation of the transcriptional regulation of the growth hormone-releasing hormone (GHRH) receptor gene, which is expressed early in terminally differentiated somatotroph cells of the anterior pituitary gland. A proximal promoter including 1.6kb 5' to the transcriptional start site is sufficient to direct tissue- and cell-specific expression of the gene in transgenic mice. Further examination of the promoter in cell culture experiments led to the identification of ten binding sites for the pituitary-specific transcription factor Pit-1. Of these ten sites with varying affinities for Pit-1, a single proximal site is necessary and sufficient for Pit-1-activated expression of the gene. The GHRH receptor is an integral molecule in regulating appropriate linear growth in vertebrates. Inappropriate expression or functioning of the GHRH receptor is associated with growth diseases, including dwarfism and gigantism or acromegaly. Another major goal of this thesis work is understanding signaling by the receptor. Post-transcriptional regulation, specifically alternative splicing, is a mechanism by which many protein products are produced from a single gene. Examination of a truncated splice variant human GHRH receptor reveals a potential role for dimerization in GHRH receptor function. The truncated GHRH receptor cannot signal through the cAMP second messenger pathway and acts in a dominant negative fashion by forming a complex with the wild-type receptor that cannot bind GHRH. This work was the first to show a role for oligomerization in modulating signaling of this receptor. Together, the work described in this thesis examines the requirements for transcriptional activation of expression of the GHRH receptor, and how the post-transcriptional process of alternative splicing affects signaling of this important molecule.

Last modified

• 05/28/2018

Creator

• Allison Therese MvElvaine

DOI

• https://doi.org/10.21985/N2G11K

Subject

• Interdepartmental Biological Sciences Program

Keyword

• Gene Regulation
• Pituitary Development
• Alternative Splicing

Date created

• 2007-05-03

Resource type

• Dissertation

Rights statement

• In Copyright