Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need

Abstract

The body responds to stress by activation of the hypothalamic-pituitary-adrenal (HPA) axis and release of glucocorticoids. Glucocorticoid production in the adult regulates carbohydrate and amino-acid metabolism, maintains blood pressure, and restrains the inflammatory response. In the fetus, exogenous glucocorticoids accelerate maturation of lung and gastrointestinal enzyme systems and promote hepatic glycogen deposition. Corticotropin-releasing hormone (CRH), a 41-amino-acid neuropeptide produced in the paraventricular nucleus of the hypothalamus and many regions of the cerebral cortex, has been implicated in both the HPA axis and behavioural responses to stress. To define the importance of CRH in the response of the HPA axis to stress and fetal development, we have constructed a mammalian model of CRH deficiency by targeted mutation in embryonic stem (ES) cells. We report here that corticotropin-releasing hormone-deficient mice reveal a fetal glucocorticoid requirement for lung maturation. Postnatally, despite marked glucocorticoid deficiency, these mice exhibit normal growth, fertility and longevity, suggesting that the major role of glucocorticoid is during fetal rather than postnatal life.

CRH: The link between hormonal-, metabolic- and behavioral responses to stress

“…CRH knockout mice have been generated in 1995 (Muglia et al 1995). CRH-KO pups born to homozygote mothers must have been supplemented by corticosterone from E12 until weaning to prevent pulmonary insufficiency.…”

The anxiolytic effect of environmental enrichment is mediated via amygdalar CRF receptor type 1

“…[7][8][9] Dysregulation of the stress response can have severe psychological and physiological consequences 10,11 and chronic hyperactivation of the CRF system has been linked to stress-related emotional disorders such as anorexia nervosa, depression and anxiety. [10][11][12][13][14][15][16][17] In addition to CRF, the mammalian CRF-peptide family contains urocortin 1, urocortin 2 and urocortin 3.…”

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

“…Genetic manipulation of each element of the CRH-system is associated with various degrees of impairment of adrenocortical structure and function. [3][4][5][6][7][8][9][10][11] CRH-deficient mice lack the normal diurnal glucocorticoid rhythm and present with adrenocortical atrophy and severely impaired glucocorticoid release to the stress of restraint, ether and fasting. 4 Similarly, CRHR1 null mice demonstrate adrenal atrophy and a reduced stress-induced secretion of corticosterone.…”