Research Program Overview

3D rendered image comparing the cranial base of an embryonic day 18.5 wildtype (white) and cleft lip/palate mutant (red) mouse3D rendered image comparing the cranial base of an embryonic day 18.5 wildtype (white) and cleft lip/palate mutant (red) mouse.

Formation of the face involves the coordinated growth and fusion of multiple embryonic tissue masses. This process requires an exquisite level of coordination of gene activities and interaction, and is likely influenced by maternal nutrition and other in utero conditions. The Cox Lab’s research aims to understand the role of genes and the impact of non-genetic factors, such as diet (for example, vitamin A and alcohol), in influencing the susceptibility to common facial conditions. Understanding individual genetic and nutritional/environmental contributions to normal facial shape is imperative if we are to more accurately predict the impact of specific deficiencies on an individual’s risk of being born with a craniofacial anomaly. The three common conditions that are currently under study in the lab are cleft lip and palate, midfacial hypoplasia and craniofacial microsomia.

Chick embryo with cleft lip due to disruption of Nectin1Chick embryo with cleft lip due to disruption of Nectin1.

Our team uses both in vitro and in vivo (mouse and chick) systems as models of human development because of the remarkable conservation of gene function and similarity in embryologic processes that form the face. Our investigations extend from biochemical and cellular characterization of how defective genes impact molecular events within cells to studies of how these cellular changes alter embryonic facial growth and the morphological changes that must occur to form a fully functional face. In addition, Dr. Timothy C. Cox is a member of an international consortium that is identifying new genes causing cleft lip and palate through the application of state-of-the-art genome level sequencing of families in which the condition presents in numerous individuals across multiple generations. These varied approaches have yielded novel insight into the causes of cleft lip and palate, and suggest that a common molecular pathway may underlie a large proportion of cleft cases.

3D rendered image of a confocal microscopy image stack showing the embryonic facial tissues preparing to fuse to form the upper lip3D rendered image of a confocal microscopy image stack showing the embryonic facial tissues preparing to fuse to form the upper lip.

Among the lab’s major research strengths are our capacity to transiently manipulate gene function within the facial epithelia of developing chick embryos and our unique capacity for high-resolution 3-D imaging and quantification of facial, bone and tooth shape both in early embryos through to postnatal ages. The latter work is facilitated by the lab’s unique access to complementary high-resolution X-ray and light-based tomographic scanners, and made possible by contributions from computer scientists that work hand-in-hand with biologists. The resultant specialized software that has been developed in the lab enables us to assess even the impact of individual gene mutations and non-genetic factors (such as dietary vitamins) on development of the face and ultimately an individual’s susceptibility to specific facial birth defects. This approach to understanding facial disorders is unique in the field.

Understanding the contribution of individual genes as well as non-genetic factors such as nutrition or environmental stressors is essential if significant improvements in the treatment of affected children are to be realized. However, an arguably greater or more tangible benefit of understanding the interaction between our genes and these non-genetic factors would be the ability to recommend maternal dietary interventions to either those at risk or as a general approach to minimize the incidence and/or severity of the various craniofacial conditions.

Research Projects in the Cox Lab

  • Understanding the cellular and developmental function of genes that coordinate the development of the lip and palate
  • Identification of new genes and molecular pathways causing cleft lip and palate in families using genome and exome sequencing technologies (as part of an international cleft consortium).
  • Quantifying the impact of genetic mutation and dietary factors on embryonic and postnatal facial development and susceptibility to cleft lip and palate.
  • Understanding the developmental mechanisms leading to midface hypoplasia.
  • Dissecting the genetic pathways and developmental mechanisms involved in two new mouse models of craniofacial microsomia.

For more information about the scanners and our imaging work, visit the Small Animal Tomographic Analysis (SANTA) facility.