Int. J. Dev. Biol. 53: 1483 - 1494 (2009)
doi: 10.1387/ijdb.072430nm
© UBC Press

Ectopic Meis1 expression in the mouse limb bud alters P-D patterning in a Pbx1-independent manner

Nadia Mercader1, Licia Selleri2, Luis Miguel Criado1, Pilar Pallares1, Carlos Parras3, Michael L. Cleary4 and Miguel Torres*1

1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III, Madrid, Spain, 2Department of Cell and Developmental Biology, Cornell University Weill Medical School, New York, USA, 3INSERM U711, Université Pierre et Marie Curie, IFR de Neuroscience, Hôpital de la Salpêtrière, Paris, France and 4Department of Pathology, Stanford University School of Medicine, Stanford, USA

ABSTRACT During limb development, expression of the TALE homeobox transcription factor Meis1 is activated by retinoic acid in the proximal-most limb bud regions, which give rise to the upper forelimb and hindlimb. Early subdivision of the limb bud into proximal Meis-positive and distal Meis-negative domains is necessary for correct proximo-distal (P-D) limb development in the chick, since ectopic Meis1 overexpression abolishes distal limb structures, produces a proximal shift of limb identities along the P-D axis, and proximalizes distal limb cell affinity properties. To determine whether Meis activity is also required for P-D limb specification in mammals, we generated transgenic mice ectopically expressing Meis1 in the distal limb mesenchyme under the control of the Msx2 promoter. Msx2:Meis1 transgenic mice display altered P-D patterning and shifted P-D Hox gene expression domains, similar to those previously described for the chicken. Meis proteins function in cooperation with PBX factors, another TALE homeodomain subfamily. Meis-Pbx interaction is required for nuclear localization of both proteins in cell culture, and is important for their DNA-binding and transactivation efficiency. During limb development, Pbx1 nuclear expression correlates with the Meis expression domain, and Pbx1 has been proposed as the main Meis partner in this context; however, we found that Pbx1 deficiency did not modify the limb phenotype of Msx2:Meis1 mice. Our results indicate a conserved role of Meis activity in P-D specification of the tetrapod limb and suggest that Pbx function in this context is either not required or is provided by partners other than Pbx1.

Keywords:

mouse limb development, proximo-distal axis, Meis1, Pbx

*Corresponding author e-mail: mtorres@cnic.es