Mice lacking Ren1c were generated using C57BL/6-derived embryonic stem cells. Mice homozygous for Ren1c disruption (Ren1c؊/؊) are born at the expected ratio, but approximately 80% die of dehydration within a few days. The surviving

Duffy antigen/receptor for chemokines (DARC) is a promiscuous receptor for chemokines that is required for Plasmodium vivax infection of erythroid cells. This receptor is expressed by subsets of endothelial, as well as erythroid cells. Selection for protection from malaria infection resulted in an erythroid-specific defect, suggesting that DARC may play a critical role in endothelial biology. Mice with targeted disruption of this gene were generated, and the function of DARC in inflammation was explored. RNA from spleens of homozygous mutant mice lacked DARC transcripts, which were abundant in wild-type (+/+) and heterozygote (+/−) mice. DARC−/− mice lacked developmental abnormalities and were healthy at 1 year. Whereas hematologic parameters were within normal ranges, erythrocytes from nullizygous mice lacked CXC and CC chemokine-binding activity. Challenge with lipopolysaccharide resulted in significantly increased inflammatory infiltrates in lung and liver of nullizygous mice. These results suggest that DARC modulates the intensity of inflammatory reactions as a sink for chemokines.

To determine whether the expression of cardiac genes changes in a graded manner or by on/off switching when cardiac myocytes change genetic programs in living animals, we have studied two indicator genes that change their expression oppositely in mouse binucleate ventricular cardiomyocytes during development and in response to cardiac hypertrophy. One is a single-copy transgene controlled by an ␣-myosin heavy chain (aMHC) promoter and coding for CFP. The other is the endogenous ␤-myosin heavy chain (bMHC) gene modified to code for a YFP-bMHC fusion protein. Using high-resolution confocal microscopy, we determined the expression of the two indicator genes in individual cardiomyocytes perinatally and after inducing cardiac hypertrophy by transverse aortic constriction. Our results provide strong evidence that the cardiac genes respond by switching their expression in an on/off rather than graded manner, and that responding genes within a single cell and within the two nuclei of cardiomyocytes do not necessarily switch concordantly.gene switching ͉ myosin heavy chain