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.