Anterior pituitary products involved in pituitary organogenesis and the mammalian stress response.

The differentiation of cell types is an important aspect of organogenesis. The five cell types in the mature anterior pituitary are distinguished by the hormones they produce. To determine the developmental relationships among these cell types, two different approaches were used. First, a transgenic ablation study was performed using the mouse alpha-GSU (malpha-GSU) promoter to direct expression of the diphtheria toxin A subunit in the anterior pituitary primordium. Only thyrotropes and gonadotropes were ablated, indicating that these cells are not required for the development of the other cell types. Second, a new approach was developed that labels cells using the cre/loxP system. Transgenic mice expressing cre recombinase under the control of the malpha-GSU promoter were mated to transgenic mice carrying a reporter construct consisting of a loxP-flanked Green Fluorescent Protein (GFP) followed by beta-galactosidase. In cells that express cre recombinase, the GFP portion of the reporter is excised, allowing translation of beta-galactosidase. The recombined gene is passed on to all of that cell's descendants, which can be identified by X-gal staining. Only thyrotropes and gonadotropes were labeled in pituitaries of doubly transgenic mice, implying that the other cell types in the anterior pituitary are not derived from alpha-GSU progenitors. Thus, commitment to specialized pituitary cell fates occurs prior to the expression of alpha-GSU. Another pituitary product, corticotropin-releasing hormone-binding protein (CRH-BP) might play a role in the modulation of the activity of CRH within the hypothalamic-pituitary-adrenal (HPA) axis. The malpha-GSU promoter was used to direct high level expression of the CRH-BP in transgenic mice. The alphaCRH-BP transgenic mice exhibit increases in CRH and vasopressin (AVP) and have normal HPA axis function, which is probably attributable to these compensatory changes. These results support the importance of CRH-BP regulation in HPA axis function. In addition, the alphaCRH-BP transgenic mice exhibit increased activity in standard behavioral tests and an altered circadian pattern of food consumption. These behavioral changes are probably caused by ectopic expression of the transgene in the brain, suggesting that regulation of CRH-BP in the brain is important in feeding or emotional responses.Ph.D.Biological SciencesMolecular biologyNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/132313/2/9963749.pd