The role of corticotropin-releasing hormone-binding protein in the murine anterior pituitary.

Abstract

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, stimulating the secretion of corticotropin releasing hormone (CRH) into the pituitary portal system. CRH, the primary neuroendocrine mediator of the mammalian stress response, activates CRH-receptors located on anterior pituitary corticotropes, causing the release of adrenocorticotropic hormone (ACTH), and subsequent secretion of glucocorticoids from the adrenal gland. CRH-Binding Protein (CRH-BP), a 37kDa-secreted glycoprotein, binds CRH with high affinity, inhibits CRH-induced ACTH secretion, and may also inhibit CRH activity at central sites of CRH release. CRH-BP is expressed in the CNS and the pituitary; however, pituitary expression is sexually dimorphic. Females exhibit dramatically elevated levels of CRH-BP mRNA, with expression not only in corticotropes, but also in lactotropes and gonadotropes. The functional significance of CRH-BP in endocrine cells associated with reproduction is poorly understood. This thesis focuses on elucidating the cellular targets of pituitary CRH signaling and the physiological role(s) of CRH-BP in corticotropes, gonadotropes, and lactotropes, including factors regulating CRH-BP expression. To identify the cellular targets of CRH signaling and the potential pituitary sites of CRH-BP:CRH interaction, I characterized the cell-specific expression of CRH receptors. CRH-R1 is expressed in corticotropes, with novel localization in a sub-set of lactotropes, gonadotropes, and thyrotropes in both sexes; interestingly, females have significantly more CRH-R1 in lactotropes than males. Acute restraint stress increases CRH-BP mRNA expression in both male and female pituitaries. In females, stress increases CRH-BP expression in both corticotropes and lactotropes, with the majority of increased CRH-BP localizing to lactotropes. My studies demonstrate that GnRH, the principal regulator of pituitary gonadotropin secretion, positively regulates CRH-BP in a gonadotrope-like cell line. These studies highlight pituitary gonadotropes and lactotropes as potential interfaces between the stress and reproductive axes. Finally, my studies on the physiological effects of CRH-BP deficiency on reproductive function in vivo suggest important roles for CRH-BP in maternal behavior. Combined, these studies highlight the pituitary as an important site of interaction between the HPA and multiple endocrine axes and identify CRH-BP as a potential modulator of endocrine interactions in the murine pituitary.Ph.D.Biological SciencesMolecular biologyNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126587/2/3253429.pd