Gene regulatory networks and craniofacial patterning in the chick

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Understanding the diversity of life on earth, and its origins, has occupied human thought for centuries. Indeed, contemplation of biological diversity and the origins of novel types of organisms is deeply significant for a species capable of reconciling its own place in life's great variety of forms. A key insight of modern evolutionary developmental biology is that, by and large, evolution proceeds through modulation of gene regulation, rather than by modulation of the genes themselves. Identifying regulatory sequences in the genomes of model organisms, understanding how they operate to regulate gene expression, and how they have changed in different animal lineages is, therefore, our best way to reconstruct pathways of macroevolution. My research program focuses on the mechanisms of action of Dlx genes (a family of six related transcription factors) and their contributions to evolutionary diversity. The genes themselves are highly conserved across animal species and they function in conserved ways in the brain, limbs, skeleton, and skin of diverse kinds of animals. My research group explores Dlx genes in a variety of these embryonic contexts, most recently in jaw patterning. Experimental loss of Dlx genes in mice and zebrafish, and naturally occurring mutations in humans, confirm that Dlx genes play a conserved role in jaw patterning in very different kinds of vertebrates and point to the likelihood that they participate in regulatory networks of genes that pattern jaws in all vertebrates. We propose to advance our knowledge of jaw development and evolution on three fronts, with Dlx genes as the initial focus. We want to test whether candidate Dlx-regulated genes in mice are directly regulated by Dlx transcription factors in the chick embryo and, if so, what DNA sequences mediate that regulation. Additionally we will identify, in an unbiased way, novel genome binding sites for Dlx proteins in jaw forming tissue in chick embryos and, thereby, the genes regulated by those sequences. We are interested in the functions of these regulatory elements on two different timescales. On the one hand, we want to understand how those elements function in individual chick embryo development in molecular detail. On the other hand, we wish to compare how the regulatory networks are similar and different among diverse kinds of living vertebrates to understand how the networks have changed over evolutionary time. For the latter objective, we will manipulate the sequences of these regulatory elements to understand how they function in the regulation of gene expression in the chick, and ask whether this is the same or different from their functions in mice. This research will advance our knowledge of jaw development in an important model system (the chick) and of gene regulation more broadly. This work will also generate novel tools to improve gene function manipulation in the chicken embryo, which may benefit the Canadian poultry industry.