Mice Carrying a Null Allele of the GR GRnulnuN Show Complete Penetrance of Perinatal Lethality

A finding that remained unexplained for a long time was the fact that about 20% of the homozygous GRhypo/hypo mutants survived to adulthood without any gross abnormalities. The discovery of two unusual GR-mRNA species in homozygous mutants provides a potential explanation for this observation (unpublished data). In one of these transcripts exon 1 is directly spliced onto exon 3 of the GR gene, thereby omitting exon 2, which codes for the entire NH2-terminus of the protein. From studies on apoptosis it is known that a methionine in exon 3 can serve as a potential start site, giving rise to a GR protein of about half the normal size consisting only of the

DNA-binding domain and the ligand-binding domain (Dieken et al, 1990). The second transcript is a fusion between the neomycin phosphotransferase-cDNA and exon 2 of the GR gene, possibly representing a polycistronic mRNA. Therefore, one cannot rule out that at least some transcriptional regulation remains in GRhypo/hypo mice, although at a strongly reduced level. In the light of these results a new GR mutant was generated (GRnul1), this time by deleting exon3 and thus ensuring complete ablation of GR protein.

Interestingly, in contrast to GRhypo/hypo carrying the hypomorphic allele, all homozygous GRnu"/nu" mice die immediately after birth, and no exceptions have been observed to date. We hypothesize that survival of some of the GRhypo/hypo mice is indeed due to a remaining truncated form of the GR and that its transcriptional properties are at the limit of what is necessary for survival. In some cases this might be sufficient to overcome the critical first hours after birth, while in other cases it might not. In summary, we conclude that the GR is absolutely necessary for survival, although a strongly reduced level of GR activity might be sufficient to overcome perinatal lethality.

Analysis of GRnull/null mice revealed only few differences compared to homozygous mutants carrying the hypomorphic allele. However, some of the phenotypes were more pronounced in GRnull/null mice than in GRhypo/hypo mice. As discussed earlier, this was especially obvious in the case of postnatal survival, but also in the case of the adrenal medulla. A major difference was observed for the skin, which is only altered in GRnull/null mice. Whereas GRhypo/hypo mice have normal skin at birth, the skin of GRnull/null mice appears unmature at birth (unpublished data). In summary, from the analysis of GRnull/null mice we conclude that the observations made in GRhypo/hypo mice are indeed characteristic for an absence of the GR during development. However, interpretation of effects observed in adult GRhypo/hypo mice requires caution, as it must be considered that a truncated GR protein may have some residual transcriptional properties.

In Table I the main phenotypes of GRhypo and GRnull mice are summarized and the few minor differences between the two alleles are mentioned in each case.

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