Characterization of CpeNeo mice, a conditional null mutation of carboxypeptidase E, and restoration of Cpe expression with Flp recombinase

ABSTRACT: Carboxypeptidase E (CPE) is an essential enzyme that contributes to the biosynthesis of the vast majority of neuropeptides and peptide hormones. Mice lacking CPE activity due either to a natural mutation or targeted disruption of the Cpe gene have greatly decreased levels of most neuropeptides and show a large number of defects including severely impaired fertility, adult-onset obesity, anxiety- and depressive-like behavior, and abnormal hippocampal development. In the present study, we generated a mouse line named CpeNeo due to a neomycin cassette within the Cpe gene that blocks normal splicing of the gene, leading to the loss of enzyme expression. CpeNeo/Neo mice show all of the defects previously found with Cpefat/fat and/or KO mice. In addition, young adult CpeNeo/Neo mice are more sensitive to morphine-induced hyperlocomotion than wild-type mice, while older CpeNeo/Neo mice are less sensitive than wild-type mice. Removal of the neomycin cassette with Flp recombinase under a germline promoter restored the expression of CPE activity, leading to normal levels of neuropeptides in brain. CpeFlp/Flp mice are identical to wild-type mice in terms of behavior and physiology. Mice heterozygous for the CpeNeo allele have Cpe mRNA levels ~50% of wild-type mice, but are identical to wild-type mice in all behaviors and physiological parameters examined. These results confirm that CPE is not a rate-limiting enzyme in the production of most neuropeptides, despite claims that small decreases in CPE activity contribute to obesity or other physiological effects

INSTRUMENT(S): Synapt G2 HDMS

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Lakshmi A. Devi   Lloyd D. Fricker  

PROVIDER: MSV000087742 | MassIVE | Thu Jul 01 18:27:00 BST 2021

REPOSITORIES: MassIVE