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Cox Lab

Current Research

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Research Program Overview

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

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

The Cox lab’s research aims to understand the role of genes and the impact of non-genetic factors, such as diet and alcohol (i.e., epigenetics), in influencing the susceptibility to common facial conditions, and in particular cleft lip and palate and midfacial hypoplasia. The Cox team uses both the 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 changes alter embryonic facial growth and the morphological changes that must occur to form a fully functional face.

Among our 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 craniofacial shape both in early embryos through to postnatal ages. This latter technology and expertise, together with our new methodologies to study the lip and palate, put the Cox lab in a unique position to advance our understanding of the causes and develop potential preventative treatment to reduce the incidence and burden of these common craniofacial malformations.

Chick embryo with cleft lip due to disruption of Nectin1

Chick embryo with cleft lip due to disruption of Nectin1.

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 genetic interactions, and is likely influenced by maternal nutrition and other in utero 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 cleft lip and palate or other craniofacial anomaly.

Research Goals: Reducing the Impact of Craniofacial Malformations

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

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

Congenital deformities of the face occur at high frequency yet their impact on society is often underappreciated. To highlight this, for every child (between the ages of 1 and 18) who is diagnosed with any form of cancer, at least four are born with a craniofacial anomaly.

Cleft lip and palate (CLP) is arguably the most well-known and recognizable facial birth defect. Although the incidence of CLP varies between different countries and even different populations within a country, in general it is no more prevalent in many third world countries as it is in the US, occurring with an average frequency of 1 in every 700 live births. Consequently, the World Health Organization has identified CLP as a global health issue.

Facial anomalies such as CLP, midface hypoplasia and craniofacial microsomia can lead to community alienation, heightened self-consciousness, low self-esteem and long-term psychological effects. Furthermore, the clinical management protocol in many cases can be lengthy, spanning well into the teenage years and involving multiple reconstructive surgeries, speech pathology, extensive dental treatment, counseling, and cosmetic operations. These factors therefore pose many additional and often immeasurable burdens on patients, families and health systems.

Expression of a GFP-MID1 fusion protein (green) in cells. Nuclear DNA is blue.

Expression of a GFP-MID1 fusion protein (green) in cells. Nuclear DNA is blue..

Although in some cases a single gene mutation inherited from generation to generation may be the primary cause of the condition, the vast majority of cases (whether of CLP or other conditions) present as an isolated finding in one individual only. In such cases, genetic and epidemiological studies on many different populations support the view that many genes, as well as dietary and environmental factors, contribute to an individual’s susceptibility to this condition. Such inherent variability in craniofacial form is typically the root cause of difficulties in accurately predicting outcomes following surgical interventions, further confounds counseling regarding risk for future pregnancies, and often also the ability of clinicians to accurately diagnose patients.

Understanding the contribution of individual genes as well as non-genetic factors such as nutrition or environmental stressors is essential if significant improvements in these clinical areas 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 major CLP genes including IRF6, the Nectins and MID1/2
  • Identification and characterization of new genes causing craniosynostosis-associated midface hypoplasia
  • Dissecting the genetic pathways involved in two new mouse models of craniofacial microsomia
  • The epigenetic impact of maternal alcohol consumption and diet on proper midfacial growth
  • Quantifying embryonic and postnatal midfacial development and the impact of genetic and epigenetic factors

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