Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Comunidad de Madrid (España), Fundación ProCNIC, Ministerio de Economía y Competitividad (España)
Vertebrate axial skeletal patterning is controlled by co-linear expression of Hox genes and axial level-dependent activity of HOX protein combinations. MEIS transcription factors act as co-factors 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. Although Raldh2 and Meis positively regulate each other, Raldh2 elimination largely recapitulates the defects associated with Meis deficiency, and Meis overexpression rescues the axial skeletal defects in Raldh2 mutants. We propose a Meis-RA-positive feedback loop, the output of which is Meis levels, that is essential to establish anterior-posterior identities and patterning of the vertebrate axial skeleton. This research was supported by the Ministerio de Ciencia, Innovación y Universidades (PGC2018-096486-B-I00), the Instituto de Salud Carlos III (RD16/ 0011/0019) and by the Comunidad de Madrid (S2017/BMD3875). The Centro Nacional de Investigaciones Cardiovasculares Carlos III is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro Centro Nacional de Investigaciones Cardiovasculares Carlos III Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). A.C.L.-D. was the recipient of a Formación Personal Investigador fellowship from the Ministerio de Economı́a y Competitividad (BES-2013-064374). Sí
