Generation and Characterisation of an HRP-3-deficient Mouse Model

Abstract

The hepatoma-derived growth factor-related protein-3 (HRP-3) is a growth factor of the HDGF protein family with neurotrophic activity. Predominantly expressed in the brain, it was shown to bind and stabilise microtubules. A function during brain development is speculated in the literature.<br /> Targeting of the HRP-3 locus has been hitherto unsuccessful. In this work, a non-conditional targeting vector targeting exon 2 of HRP-3 was designed and a mutant mouse line was successfully created. Mice were viable and fertile and lived up to the age of ten months without any obvious abnormalities. A single case of a six-month-old mouse with small lesions in the cerebral cortex was found, but due to the absence of older animals, these results were not reproduced. <br /> Using this mouse model, it was discovered that HRP-3 is indeed predominantly expressed in the brain, but also, in contrast to findings in contemporary literature, to lesser extent in a range of other tissues and specific cell types. These include podocytes in the kidney and heart muscle cells. It can thus be supposed that the function of HRP-3 is not only confined to the brain, but also extends to other organs. Additionally, it was also shown that expression of HRP-3 within the brain extends to more cell types than previously reported. <br /> Furthermore, HRP-3-deficient animals exhibited a hyperplasia of stomach mucosa and submucosa, resulting in extreme stomach folds. Since it was shown here that HRP-3 is expressed in several cell types in the stomach, a phenotype is conceivable. A reason for these foldings was not yet found and remains to be elucidated. Hyperplasia of the stomach mucosa is characteristic for the human Ménétrier disease. Whether HRP-3-deficient mice resemble such a disease is object for further analyses. <br /> In summary, an HRP-3-deficient mouse model was successfully created and first analyses were able to give new HRP-3 expression data. A more extensive analysis, especially of the stomach abnormalities, is necessary and might provide new insights into the function of HRP-3.