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Presenting Author(s) Aimée Zuniga
Abstract Title Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression.
Full author List Aimée Zuniga 1, 2, Odyssé Michos 1, 2, François Spitz 3, Anna-Pavlina G. Haramis 4,5, Lia Panman 2, Kristina Vintersten 4, 6, Christian Klasen 4, William Mansfield 4, Sylwia Kuc 2, Denis Duboule 3 ,Rosanna Dono 2 and Rolf Zeller 1,2
Text of abstract 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 carboxy-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 phenotype are cast as targeted disruption of its carboxy-terminal domain does not affect embryogenesis. In contrast, deletion of the corresponding genomic region reproduces the ld limb phenotype and causes allelism to mutations in Gremlin. Yet, a Gremlin null mutation in the mouse generated by gene targeting causes, in addition to an ld phenotype, neonatal lethality due to lack of kidneys and lung septation defects. 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 a large genomic landscape harboring this GCR, which is required for tissue-specific co-expression of these two structurally and functionally unrelated genes.
Which session is your work most relevant to: Limb patterning