TFAP2 transcription factors in midface development, evolution, and dysplasia

The faces found across the animal kingdom are highly diverse in shapes and forms, but remarkably they are formed by a common genetic blueprint during embryonic development. The genes organizing the face are found within “neural crest” embryonic stem cells that give rise to the bone and cartilage of the face. Despite our understanding of the genes and pathways controlling face formation, a few gaps exist in our knowledge. First, we do not know how neural crest cells fully commit to their identities to form an organized skeleton in the face; second, how such genes are connected into discrete circuits to shape the face (specifically the “midface” made of the forehead, nose, and cheeks) remains poorly understood.

Importantly, disruption of these programs leads to the high prevalence of craniofacial birth anomalies. These diseases cost hundreds of thousands of dollars for surgery, speech therapies, amongst other secondary challenges. Thus, connecting midface genes is important for not only appreciating the diversity in faces, but also understanding how facial disorders arise to better innovate future treatment and prevention strategies.

Using mouse and zebrafish genetics with modern molecular biology strategies, this dissertation investigates how genes called TFAP2 participate in the midfacial neural crest gene circuits. Specifically, we genetically removed TFAP2 genes and examined how this changes the embryo’s face, the neural crest’s behavior, and the genetics programs in them. The main finding is that TFAP2 is responsible for helping turn on midface genes like ALX, whose loss results in frontonasal dysplasia in humans and other animals. Together, this work begins connecting the dots in the mysterious genetic networks underlying midfacial development, shape diversity, and disease.