Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis transcription factors and retinoic acid

Abstract

Vertebrate axial skeletal patterning is controlled by collinear expression of Hox genes and axial level-dependent activity of HOX protein combinations. MEIS transcription factors act as cofactors of HOX proteins and profusely bind to Hox complex DNA, however their roles in mammalian axial patterning remain unknown. Retinoic acid (RA) is known to regulate axial skeletal element identity through the transcriptional activity of its receptors, however, whether this role is related to MEIS/HOX activity remains unknown. Here, we study the role of Meis in axial skeleton formation and its relationship to the RA pathway in mice. Meis elimination in the paraxial mesoderm produces anterior homeotic transformations and rib mis-patterning associated to alterations of the hypaxial myotome. While Raldh2 and Meis positively regulate each other, Raldh2 elimination largely recapitulates the defects associated to Meis-deficiency and Meis overexpression rescues the axial skeletal defects in Raldh2 mutants. We propose a Meis-RA positive feedback loop whose output is Meis levels and is essential to establish anterior-posterior identities and pattern of the vertebrate axial skeleton.