Glucocorticoid receptor knockout mice

Two distinct disruptions of the GR gene were generated in mice using standard gene targeting. In one model (GRnu" mice), the GR gene is disrupted at exon 3, which encodes a portion of the DNA binding domain. This mutation results in complete inactiva-tion of GR leading to respiratory distress and perinatal mortality caused by severe lung atelectasis (Cole et al, 1995; Kellendonk et al, 1999). Thus, glucocorticoid signaling through GR is critically needed for lung maturation and neonatal survival.

Unfortunately, early mortality in this model has precluded extensive investigation into specific mechanisms of glucocorticoid modulation of lung development. CRF KO mice exhibit a similar phenotype but are more amenable for study because mortality can be rescued with prenatal glucocorticoid treatment (Muglia et al, 1995, 1999). In a second model (GRhypo mice), exon 2 is disrupted, resulting in the expression of an mRNA splice variant that leads to a truncated protein with both DNA- and ligand-binding domains intact. While these mice share the same fate as GRnu" mice, the severity and penetrance are reduced, thus 5-10% of mice survive allowing for some testing in adult animals (Cole et al, 1995).

Feedback regulation of the HPA cascade is severely impaired in these models. CRF mRNA expression in the PVN as well as CRF immunoreactivity in the median eminence is significantly elevated, resulting in elevated levels of circulating ACTH and cortiosterone. Interestingly, vasopressin content remained unchanged, suggesting that CRF is the primary target of GR-mediated negative feedback (Kretz et al, 1999). Morphology of the adrenal glands reveals substantial hypertrophy of the cortex and the lack of a solid medulla (Cole et al, 1995). Thus, these models have been used for in-depth study of GR activation on medulla chromaffin cell development (Finotto et al, 1999) with the surprising discovery that GR signaling is not necessary for chromaffin differentiation as previously thought. Behavioral measures indicate that surviving adult GRhypo mice have impaired processing of spatial but not visual information (Oitzl et al, 1997). These results are consistent with findings in GR antisense knock-down animals (see below) and support a role for GR in modulating spatial memory.

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