Meis Transcription Factor in Axial Development

Abstract

Metazoan antero-posterior patterning is established during development and in vertebrates its organization can be studied through the specific morphologies of vertebrae depending on their position along the rostro-caudal axis. Hox genes encode DNA-binding homeodomain transcription factors essential for the specification of axial skeletal identities. The specificity and affinity of Hox proteins in DNA binding and axial identity specification depends on interactions with cofactors. Meis transcription factors form different molecular complexes required for Hox proteins to efficiently regulate their targets. In this thesis we show that Meis is involved in the specification of axial identities and skeletal patterning, by showing that the deletion of Meis produces anterior homeotic transformations and other skeletal defects affecting the occipital, cervical, thoracic and anterior lumbar region. The abnormalities observed in the skeleton of Meis-deficient mice do not involve changes in Hox gene expression, despite the extensive binding of Meis to Hox genetic complexes, and therefore, their role as Hox cofactors could underlie the homeotic functions described. Through molecular analyses, we found retinoic acid signaling deficiencies in Meis mutants and identified the gene Raldh2, which codifies for the main embryonic retinoic acid synthesizing enzyme, as a putative direct Meis target. A compared analysis of Meis and Raldh2 mutants identifies similar alterations of the skeletal pattern, which suggests that, at least in part, Meis roles in axial skeleton patterning are conveyed by regulation of the retinoic acid pathway. Besides homeotic transformation, we found defective patterning of the distal segments of ribs, which we correlated with defects in molecular pathways required for hypaxial muscle development. The results presented characterize the functions of Meis genes in axial skeletal patterning and identify molecular pathways by which they perform these functions.