Regulatory mechanisms controlling pattern formation in the vertebrate embryo

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My ongoing research program aims to discover how the vertebrate body plan is established. A segmented body plan is a common feature of many metazoan organisms. In vertebrates, segmentation is evident in the vertebral column, spinal nerves and musculature of the trunk. The blueprint for this pattern is established by metameric structures called somites. These tissues form from unsegmented paraxial mesoderm that organizes into epithelial spheres lying bilaterally along the neural tube. Somites form in a tightly regulated temporal and spatial sequence with somites added every 30 minutes in zebrafish, and every 2 hours in mice, as the embryo extends posteriorly. Morphogen gradient establish early body axis information. These molecules initiate signal transduction cascades that converge on transcriptional regulatory proteins which then interpret this information into changes in gene expression. My goal for the next 5 years focuses on how gene regulatory events controls paraxial mesoderm specification to form somites. Previous functional studies show that transcription factors belong to the Forkhead box C family (FOXC) are essential regulators for somite formation. Foxc genes are expressed in paraxial mesoderm (PM) and throughout all somites during zebrafish and mouse development. Loss of foxc1a function in zebrafish disrupts the formation of first 8-10 somites in the anterior of the embryo but somites forming in the posterior appear unaffected. Loss of both Foxc1 and Foxc2 function in mice causes embryonic lethality at 9.5 days post coitum and results in the absence of segmented somites. These mice arrest in development at a stage where only the anterior somites form, thus it is not known whether these Foxc genes are required for somite formation in the posterior of the embryo. My hypothesis is that Foxc genes (Foxc1 and Foxc2 in mice; foxc1a in zebrafish) function preferentially for the specification and formation of anterior somites despite their presence in the posterior somites. I propose that factors present in the posterior PM and somites, inactivate Foxc function or compensate for its loss of Foxc function. My short-term research goals will address the following two fundamental questions to discover the mechanisms of how Foxc genes regulate the formation of somites in mice and zebrafish. 1. What are the different requirements for Foxc TFs during specification and formation of anterior versus posterior somites? 2. Do differences in gene expression exist in the PM that forms anterior somites vs posterior somites? My research program will use loss of function experiments in zebrafish and mice to discover the transcriptional regulatory mechanisms that Foxc genes participate in to form somites. This work will also provide key discoveries into formation of anterior vs posterior somites as well as uncover mechanistic differences that may occur in somitogenesis in aquatic vs terrestrial vertebrates.