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PLoS One. 2017 May 3;12(5):e0175673. doi: 10.1371/journal.pone.0175673. eCollection 2017.

Analysis of transcription factors expressed at the anterior mouse limb bud.

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Department of Systems Biomedicine, National Institute of Child Health and Development, Setagaya, Tokyo, Japan.
Department of Systems BioMedicine, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
Division of Molecular and Developmental Biology, National Institute of Genetics, and Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Mishima, Shizuoka, Japan.
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.
Department of Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.


Limb bud patterning, outgrowth, and differentiation are precisely regulated in a spatio-temporal manner through integrated networks of transcription factors, signaling molecules, and downstream genes. However, the exact mechanisms that orchestrate morphogenesis of the limb remain to be elucidated. Previously, we have established EMBRYS, a whole-mount in situ hybridization database of transcription factors. Based on the findings from EMBRYS, we focused our expression pattern analysis on a selection of transcription factor genes that exhibit spatially localized and temporally dynamic expression patterns with respect to the anterior-posterior axis in the E9.5-E11.5 limb bud. Among these genes, Irx3 showed a posteriorly expanded expression domain in Shh-/- limb buds and an anteriorly reduced expression domain in Gli3-/- limb buds, suggesting their importance in anterior-posterior patterning. To assess the stepwise EMBRYS-based screening system for anterior regulators, we generated Irx3 transgenic mice in which Irx3 was expressed in the entire limb mesenchyme under the Prrx1 regulatory element. The Irx3 gain-of-function model displayed complex phenotypes in the autopods, including digit loss, radial flexion, and fusion of the metacarpal bones, suggesting that Irx3 may contribute to the regulation of limb patterning, especially in the autopods. Our results demonstrate that gene expression analysis based on EMBRYS could contribute to the identification of genes that play a role in patterning of the limb mesenchyme.

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