Disruption of Wnt production in Shh lineage causes bone malformation in mice, mimicking human Malik–Percin‐type syndactyly

• Published in: FEBS letters 2018-02, Vol.592 (3), p.356-368
• Main Authors: Zhu, Xiao‐Jing, Fang, Yukun, Xiong, Yanan, Wang, Min, Yang, Xueqin, Li, Yan, Zhang, Xiaoyun, Dai, Zhong‐Min, Qiu, Mengsheng, Zhang, Ze, Zhang, Zunyi
• Format: Article
• Language: English
• Subjects: Animals; Body Patterning; Cell Lineage; Cells, Cultured; Disease Models, Animal; Fingers - abnormalities; Gene Deletion; Gene Expression Regulation, Developmental; genetic animal models; hedgehog; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; limb patterning; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mice; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; syndactyly; Syndactyly - genetics; Toes - abnormalities; Wnt signaling; Wnt Signaling Pathway
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.12963

Here, we show that Shh‐Cre‐mediated deletion of Wntless, the Wnt cargo protein, in mouse posterior limb mesenchyme causes bone syndactyly of the 3rd and 4th digits, resembling the human Malik–Percin type. The Shh descendants gradiently distributed from digit 5 to posterior half of digit 3 in wild‐type limbs, however, they abnormally increased in posterior digit 3 in WntlessShh‐Cre. WntlessShh‐Cre limbs displayed altered expression of hedgehog pathway genes and impaired noncanonical Wnt signaling activity. We further showed that the anterior limb mesenchymal cells in the WlsShh‐Cre served as a source of Wnt5a to reorientate the adjacent Wls‐lacking Shh lineage cells to move anteriorly and subsequently led to syndactyly, suggesting that aberrant mesenchymal cell movement/condensation may underlie the pathogenesis of syndactyly.