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Conserved regulation of proximodistal limb axis development by Meis1/Hth

Nature volume 402, pages 425–429 (1999)Cite this article

Abstract

Vertebrate limbs grow out from the flanks of embryos, with their main axis extending proximodistally from the trunk. Distinct limb domains, each with specific traits, are generated in a proximal-to-distal sequence during development1. Diffusible factors expressed from signalling centres promote the outgrowth of limbs and specify their dorsoventral and anteroposterior axes2,3,4. However, the molecular mechanism by which limb cells acquire their proximodistal (P–D) identity is unknown1. Here we describe the role of the homeobox genes Meis1/2 and Pbx1 in the development of mouse, chicken and Drosophila limbs. We find that Meis1/2 expression is restricted to a proximal domain, coincident with the previously reported domain in which Pbx1 is localized to the nucleus5, and resembling the distribution of the Drosophila homologues homothorax (hth)5,6 and extradenticle (exd)7; that Meis1 regulates Pbx1 activity by promoting nuclear import of the Pbx1 protein; and that ectopic expression of Meis1 in chicken and hth in Drosophila disrupts distal limb development and induces distal-to-proximal transformations. We suggest that restriction of Meis1/Hth to proximal regions of the vertebrate and insect limb is essential to specify cell fates and differentiation patterns along the P–D axis of the limb.

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Figure 1: Coordinated Meis/Pbx expression in the limb bud.
Figure 2: Meis1 overexpression disrupts distal limb development in the chick.
Figure 3: Evidence for the proximalization of skeletal elements in Meis1-infected limbs.
Figure 4: Alterations in distal nerve and muscle patterning in Meis1-infected limbs.
Figure 5: Ectodermal proximalization.

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Acknowledgements

We thank P. Bovolenta and Á. Nieto for advice and help during the development of this project; Á. Nieto, D. R. Jones and C. Mark for critical reading of the manuscript; J. C. Izpisúa-Belmonte for unpublished results; and N. Copeland, J. C. Izpisúa-Belmonte, R. S. Mann and C. Tabin for probes. N.M. is a recipient of an ETH-CSIC collaborative fellowship and an EU Marie Curie predoctoral fellowship. N.A. and G.M. are supported by grants from the Spanish Dirección General de Investigación Cientifica y Técnica and Human Frontiers Program. The Department of Immunology and Oncology was founded and is supported by the Spanish Research Council (CSIC) and Pharmacia & Upjohn.

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Authors and Affiliations

  1. Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, CSIC-UAM, Madrid, E-28049, Spain

    Nadia Mercader, Esther Leonardo, Antonio Serrano, Carlos Martínez-A & Miguel Torres

  2. Centro de Biología Molecular, CSIC-UAM, Universidad Autónoma de Madrid, Madrid, E-28049, Spain

    Natalia Azpiazu & Ginés Morata

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  1. Nadia Mercader
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Correspondence to Miguel Torres.

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Mercader, N., Leonardo, E., Azpiazu, N. et al. Conserved regulation of proximodistal limb axis development by Meis1/Hth. Nature 402, 425–429 (1999). https://doi.org/10.1038/46580

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