The extreme anterior domain coordinates brain and craniofacial development

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.The head is one of the most complex and important parts of the body. The shape of the head is largely determined by the size of the brain and morphology of the facial skeleton. These tissues consist of different cell types and undergo distinct developmental programs. However, development of the brain and various parts of the face may be coordinated so that tissues form in the correct order and scale to each other appropriately. Work presented here demonstrates that the Xenopus Extreme Anterior Domain (EAD), a group of 500 cells located at the anterior tip of the frog embryo, coordinates brain and craniofacial development through two distinct mechanisms. First, the EAD acts as a long range organizer for head development by regulating the size of both the brain and surrounding facial cartilage. Perturbing expression of frzb and crescent, genes encoding Wnt antagonists, in the EAD is sufficient to decrease cell proliferation in the brain and neural crest. Analysis of transgenic reporter embryos suggests that the EAD affects beta-catenin Wnt signaling over a range of 800 microns. By affecting the growth of both the brain and neural crest-derived cartilage, the EAD determines the overall size of the head. Second, the EAD synchronizes neural crest migration and the formation of two columns of cells, termed the pre-mouth array, that precede mouth opening. During this process, Kinin-Kallikrein signaling from the EAD is required to guide neural crest cells into the face. After their migration, neural crest cells signal back to the EAD to regulate pre-mouth array morphogenesis via Wnt/PCP signaling. Formation of the pre-mouth array involves convergent extension-like behavior where the EAD, originally a wide and short mass of cells, narrows and lengthens to form two columns of cells which later split down the middle during mouth opening. Reciprocal signaling between the EAD and neural crest ensures that mouth opening begins after the neural crest have completed migration. The organizing function of the EAD is likely conserved in vertebrates including humans. Understanding global coordination of brain and craniofacial development provides insight into the causes of facial abnormalities and microcephaly.by Justin Chen.Ph. D