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RESEARCH PAPER

Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression

¹ Developmental Genetics, Department of Clinical-Biological Sciences, University of Basel Medical School, CH-4056 Basel, Switzerland; ² Department of Developmental Biology, Utrecht University, NL-3584CH Utrecht, The Netherlands; ³ Department of Zoology and Animal Biology, National Center of Competence in Research `Frontiers in Genetics' University of Geneva, CH-1211 Geneva, Switzerland; ⁴ European Molecular Biology Laboratory, D-69117 Heidelberg, Germany

The mouse limb deformity (ld) mutations cause limb malformations by disrupting epithelial–mesenchymal signaling between the polarizing region and the apical ectodermal ridge. Formin was proposed as the relevant gene because three of the five ld alleles disrupt its C-terminal domain. In contrast, our studies establish that the two other ld alleles directly disrupt the neighboring Gremlin gene, corroborating the requirement of this BMP antagonist for limb morphogenesis. Further doubts concerning an involvement of Formin in the ld limb phenotype are cast, as a targeted mutation removing the C-terminal Formin domain by frame shift does not affect embryogenesis. In contrast, the deletion of the corresponding genomic region reproduces the ld limb phenotype and is allelic to mutations in Gremlin. We resolve these conflicting results by identifying a cis-regulatory region within the deletion that is required for Gremlin activation in the limb bud mesenchyme. This distant cis-regulatory region within Formin is also altered by three of the ld mutations. Therefore, the ld limb bud patterning defects are not caused by disruption of Formin, but by alteration of a global control region (GCR) required for Gremlin transcription. Our studies reveal the large genomic landscape harboring this GCR, which is required for tissue-specific coexpression of two structurally and functionally unrelated genes.

[Keywords: cis regulation; Formin; global control region; Gremlin; limb development; regulatory landscape]

Received February 8, 2004; revised version accepted May 5, 2004.

Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.299904.

⁵ Present address: Hubrecht Laboratorium, NL-3584 CT Utrecht, The Netherlands

⁶ Present address: Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Stem Cell Mutagenesis Laboratory, Toronto, Ontario M5G 1X5, Canada

⁷ Present address: Development and Pathology of the Nervous System, Institut de Biologie du Développement de Marseille Campus de Luminy, Case 907, F-13288 Marseille CEDEX 09, France.

⁸ Corresponding author. E-MAIL Rolf.Zeller{at}unibas.ch; FAX 41-16-267-3959.

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