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Submitted on September 30, 2004
Accepted on April 28, 2005
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA 70112; Howard Hughes Medical Institute, University of Chicago, 5841 South Maryland Avenue, MC1028, Chicago, IL 60637; Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854
* To whom correspondence should be addressed. E-mail: ilindb{at}LSUHSC.edu.
Two null mouse models have previously been created to study the role of the prohormone convertase PC2 and its helper protein 7B2; unexpectedly, the phenotypes of these two nulls differ profoundly, with the 7B2 but not the PC2 null dying at 5 weeks. The genetic backgrounds of these two models differ, with the 7B2 null in a 129/SvEv (129) background and the PC2 null in a mixed C57BL/N6: 129/SvEv (B6:129) background. Since background can contribute greatly to phenotype, we have here examined strain influence on the hypothalamo-pituitary-adrenal (HPA) axis and glucose levels in wild-type (WT), 7B2 null and PC2 null mice. wild-type B6 and 129 mice differed in basal corticosterone and glucose levels. When 7B2 nulls were transferred onto the B6 background they survived and showed greatly decreased circulating corticosterone and increased blood glucose levels, most likely due to the comparatively higher adrenal resistance of the B6 strain to ACTH stimulation. Circulating ACTH levels were increased over wild-type in the B6 7B2 null, but did not reach levels as high as the 129 7B2 null. Conversely, when the mixed-strain PC2 nulls were bred into the 129 background, at the N6 generation they began to exhibit the Cushing's-like phenotype characteristic of 129 7B2 null mice and died before 6 weeks of age. Taken together these results indicate that background effects are critical, as they increase the phenotypic differences between the 7B2 and PC2 nulls and play a life-or-death role in the ACTH hypersecretion syndrome present in both 129 nulls.
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