Grant: CIHR Fellowship

Birth defects occur when the development of the embryo or fetus goes awry, often due to a genetic abnormality. Craniofacial birth defects involving the lateral face are among the most frequently observed defects seen in children treated in craniofacial centers, but they are highly variable. We propose that these birth defects are often caused by abnormalities in the parts of chromosomes that regulate genes, called enhancers, which are normally bound and controlled by regulatory proteins. Until now, our understanding of the contribution of such enhancers has been poor. However, the Genome Project has provided new tools that make experiments in this area feasible. Our proposed research aims to identify regulatory programs (enhancers and the proteins that bind them) responsible for development of the lateral face, including the external ear. For this project I have chosen to focus on the Hmx1 gene. Defects in Hmx1 have been shown to result in ear malformations in mice, rats, cattle and humans. We propose that Hmx1 and the genes it regulates occupy a central position in the development of the embryonic tissue that contributes to the ear and lateral face. I will work with experts from the Genome Project to apply a newly developed method for recognizing regulatory sequences in cells from human and mouse embryonic facial tissue. Comparing the regulatory enhancers present in both species will help distinguish meaningful sequences in the DNA that play critical, conserved roles in development of the ear and face. I will also sequence RNA from the Hmx1 "knockout" mouse, a model of a human craniofacial syndrome, to identify downstream genes involved in the development of lateral facial tissues such as the lower jaw, external ear and supporting structures. We anticipate that the regulatory targets of Hmx1 will define a pathway for lateral craniofacial development and become candidates for the causative genes in patients with birth defects involving the ear and lateral head.