“The role of ETS-1 in the Neural Crest in Cardiac Development and Disease”

Doctor's Name: 
Paul Grossfeld, MD
The Regents of the University of California

Congenital heart disease is the most common form of human birth defect, affecting almost 1% of all newborn infants.  There is now overwhelming evidence indicating that most congenital heart defects are due to a genetic cause.  Consequently, in order to improve our treatment of patients with congenital heart disease, we need to focus our efforts on understanding which specific genes cause each kind of heart defect, how these genes function during normal heart development, and how altering (mutating) these genes causes the heart defects.


Because of the limitations of performing such studies on human patients, other experimental systems must be utilized.  The mouse has become such a system, primarily due to the overall similarity of the mouse heart to the human heart, the similarity of the specific genes involved in heart development between mice and humans, the relative ease by which genetic manipulations can be performed, and the ability to characterize how altering genes affects heart development.


 Recently, there has been remarkable progress on identifying genes in mice that are involved in heart development.  Studies have demonstrated that mutating such genes leads to impaired heart development, resulting in congenital heart defects similar to those that occur in human. In a few cases, genes thought to cause human congenital heart defects were subsequently mutated in the mouse, resulting in similar congenital heart defects in the mouse.  Consequently, generation of such mouse models for human congenital heart defects enable studies to be performed that will provide critical insights into the mechanisms of congenital heart disease, and that are of direct relevance to human patients.


We have focused our studies on a rare genetic disorder, Jacobsen syndrome (11q-).  This disorder is caused by the loss of a region at the end of chromosome 11.  Remarkably, we have determined that most of the congenital heart defects that occur in the general population occurs in patients in 11q-.  Consequently, understanding the mechanisms of how congenital heart defects are caused in 11q- will provide valuable insights into most forms of congenital heart disease that occur in the general population, potentially more than for any other known genetic disorder.


Our studies on 11q- patients led to the identification of a very small region in chromosome 11 that is deleted in ALL 11q- patients that have congenital heart disease.  We then found that when one gene in this gene, ETS-1, is specifically deleted in mice, the mice have some of the same heart defects that occur in 11q- patients, specifically a hole in the heart (ventricular septal defect), and an abnormally developed left ventricle.  Although little is known about the function of ETS-1 in mammalian heart development, studies in a simple organism called the sea squirt have demonstrated that ETS-1 plays a vital role in heart development in that organism.  Remarkably, ETS-1 has been shown to regulate three genes in the sea squirt that, when mutated, have been associated with human congenital heart defects.  Understanding how loss of the ETS-1 gene causes congenital heart defects will have extremely important implications for the treatment and prevention of most forms of congenital heart disease.


 Accordingly, in this proposal we have two specific aims.  The first is to characterize in greater detail the exact heart abnormalities caused by loss of the ETS-1 gene in mice.  This will consist of utilizing techniques that will allow us to define in detail the structure of the hearts of mice lacking the ETS-1 gene.  The second specific aim will focus on understanding how loss of ETS-1 causes congenital heart defects.  In the sea squirt, one of the functions of ETS-1 in heart development is the regulation of how cells migrate to their final destination, and give rise to the final structures of the heart.  Preliminary studies already suggest a critical role for ETS-1 in regulating one essential population of cells that migrate and form the structures of the heart:  neural crest cells.  Consequently, the focus of our studies will be on determining how loss of ETS-1 impairs neural crest cell function, and its role in causing heart defects.


The results of these studies will provide extremely important insights into normal heart development, and into the mechanisms underlying some of the most common forms of congenital heart disease.  This knowledge will allow us to design strategies for improving the treatment, and even prevention, of congenital heart defects in humans.  For example, previous studies have demonstrated that neural crest cells require the chemical serotonin for normal function.  The results of our studies will allow us to formulate specific strategies, such as maternal serotonin treatment during pregnancy that could help to prevent some forms of congenital heart disease. 

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