Findings published in today's edition of Cell report that the protein, named Homeodomain-Only Protein (HOP) by the researchers, is active in controlling heart growth at various stages of development in mice. Dr. Eric Olson, chairman of molecular biology at UT Southwestern and the study's principal investigator, said the team set out to find proteins unique to the heart and study their functions. After they identified HOP, they bred mice that were genetically unable to produce the protein, with dramatic results.
"We created knockout mice lacking the gene to produce this protein, and they fell into two classes they either died as embryos because their hearts didn't grow, or they survived to adulthood with too many cardiac muscle cells," said Olson, director of the Nancy B. and Jake L. Hamon Center for Basic Research in Cancer and the Nearburg Family Center for Basic Research in Pediatric Oncology.
"Understanding the mechanisms that regulate growth of heart cells has important implications for eventual therapies directed toward repairing the damaged heart," Olson said.
Observed problems during the fetal stages of the mutant mice included numerous ruptures of the ventricular walls, thin heart chamber layers and blood in the fibrous tissue surrounding the heart. After birth, there were elevations as much as 19-fold in the number of growing cardiac muscle cells in mutant compared to wild-type mice, and gene profiling showed that 179 genes had elevated expression and 90 genes had reduced expression.
The researchers believe that HOP works by controlling levels of serum response factor (SRF), a gene-activating protein, during heart development. SRF and three sibling proteins form a group called the MADS-box, and those proteins trigger genetic a
Contact: Wayne Carter
UT Southwestern Medical Center