The Simon laboratory has a longstanding interest in limb and heart development and disease mechanisms resulting from problems that occur during these embryonic stages. In addition, the lab is studying regenerative repair of mature tissues during adulthood, concentrating on skeletal and cardiac muscle. In a recent publication, our research work revealed that a regeneration-specific matrix is embedding the cells at the site of tissue damage and instructing specific regenerative processes.
This research aims at the characterization of yet unknown gene and cell regulatory pathways that are critical in organ formation and disease. A deeper understanding of the respective gene and protein functions may result in the identification of new promising therapeutic targets for disease intervention and new opportunities for the enhancement of regenerative responses in humans; thus, it potentially will have great impact on clinical care.
Current Research Projects
Cardiac Valve Formation and Disease Mechanisms
Using zebrafish and mouse models, the lab is pursuing questions concerning cardiovascular development and disease mechanisms. In particular, the group has focused on the functional relationship between Tbx transcription factors and the actin-binding protein Pdlim7 and the role they play in these processes. Mutations in Tbx transcription factors are known to cause serious cardiac and limb malformations in humans (e.g. Holt-Oram syndrome, ulnar-mammary syndrome). We, therefore, focused on Tbx transcription factor regulation and established that all Tbx family members are nuclear/cytoplasmic shuttling proteins, meaning that they shuttle continuously back and forth carrying key information between the nucleus and cytoplasm of the cell. Specifically, we determined that Pdlim7 binds to and retains the Tbx4 or 5 proteins at the cytoskeleton and in this way controls the availability of the transcriptions factors in the nucleus to activate target genes.
Forced misregulation of Pdlim7 in the zebrafish model revealed altered expression of a number of heart-specific genes along with defects in heart development, particularly, cardiac looping and valve formation. These findings prompted the lab to generate a strain of mice with a genetic inactivation of Pdlim7 to perform a more detailed investigation of the protein’s function in the mammal. The “Pdlim7 knockout mouse” recapitulates the cardiac valve malformations (Figure 2), but in addition provides new insights into disease mechanisms that manifest only later in life and thus are of high clinical relevance.
Model Organisms and Methodologies
To address questions in congenital cardiovascular conditions and regenerative repair we are employing complementary vertebrate model systems. For our developmental studies, we are using the chicken which allows direct manipulation of the embryo in ovo; the zebrafish because the small and transparent embryos facilitate live imaging of the developing organism’s organs and cells; and the mouse because of superior technologies available for genetic manipulation. For our regeneration studies, we take advantage of the unique ability of adult zebrafish and newts, as these species can regenerate complete limbs and heart ventricular muscle throughout their lifetimes.
In order to understand the underpinning functional mechanisms at the organismal, cellular, and molecular level, the laboratory is using a range of molecular biology and genetic techniques to engineer genes for functional testing in vivo, biochemistry techniques to determine the encoded protein structure and function, and cell biological techniques to visualize tissue morphology, spatiotemporal mRNA and protein expression patterns as well as subcellular localizations of mRNA and proteins.
Erin Quick, BA
Student Intern, Northwestern University
Student Intern, Northwestern University
Stanley Manne Children's Research Institute
225 East Chicago Avenue, Box 204
Chicago, Illinois 60611-2605