Elucidation of a Brachyury-independent branch of the notochord gene regulatory network

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PROJECT SUMMARY/ABSTRACT During the early development of human and other vertebrate embryos, the notochord supports and instructs the formation of the body plan by patterning the central nervous system, paraxial mesoderm, endoderm and the numerous organs that they give rise to. Impairments in notochord formation cause birth defects and congenital skeletal malformations, while postnatally, alterations in the notochord remnants encased within the intervertebral discs are the main cause of discopathies and can give rise to rare tumors called chordomas. We are using the simple chordate Ciona to reconstruct the essential, evolutionarily conserved genetic toolkit of the notochord, with the ultimate goal of applying our findings to vertebrate development and human embryogenesis. We have shown that the notochord expression of a large number of vertebrate genes is conserved in Ciona and we have found that several Ciona notochord enhancers, the genetic switches that control notochord gene expression, share transcription factor binding sites with notochord regulatory regions that had been identified in vertebrates. Our published results provide ample evidence that the simple Ciona notochord expresses transcription factors (TFs) that are evolutionarily conserved in vertebrates, including humans, and are necessary for the development of this structure. The objective of this project is to study in detail one of these TFs, Ciona Lmx-like, and to clarify its role in notochord development. This objective will be achieved through the following experimental approaches: the elucidation of the role of Lmx-like in notochord morphogenesis (Aim 1); the identification of the notochord genes controlled by Lmx-like, and the functional characterization of a select group of them (Aim 2). Completion of these studies will shed light on an evolutionarily conserved TF, Lmx-like, which appears to act in parallel with Brachyury, the main regulator of notochord formation, and will provide a first insight into its role in notochord development. The expected results will shed light on the complex gene regulatory network that orchestrates notochord formation across chordates, and will provide a molecular blueprint for the interpretation of notochord-derived birth defects.