Syndactyly in a novel Fras1rdf mutant results from interruption of signals for interdigital apoptosis

Elizabeth A. Hines, Jamie M. Verheyden, Amber J. Lashua, Sarah C. Larson, Kelsey Branchfield, Eric T. Domyan, Juan Gao, Julie F. Harvey, John C. Herriges, Linghan Hu, David J. Mcculley, Kurt Throckmorton, Shigetoshi Yokoyama, Akihiro Ikeda, Guoliang Xu, Xin Sun

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background: Fras1 encodes an extracellular matrix protein that is critical for the establishment of the epidermal basement membrane during gestation. In humans, mutations in FRAS1 cause Fraser Syndrome (FS), a pleiotropic condition with many clinical presentations such as limb, eye, kidney, and craniofacial deformations. Many of these defects are mimicked by loss of Fras1 in mice, and are preceded by the formation of epidermal blisters in utero. Results: In this study, we identified a novel ENU-derived rounded foot (rdf) mouse mutant with highly penetrant hindlimb soft-tissue syndactyly, among other structural defects. Mapping and sequencing revealed that rdf is a novel loss-of-function nonsense allele of Fras1 (Fras1rdf). Focusing on the limb, we found that the Fras1rdf syndactyly phenotype originates from loss of interdigital cell death (ICD). Despite normal expression of bone morphogenetic protein (BMP) ligands and their receptors, the BMP downstream target gene Msx2, which is also necessary and sufficient to promote ICD, was down-regulated in the interdigital regions of Fras1rdf hindlimb buds. Conclusions: The close correlation between limb bud epidermal blistering, decreased Msx2 expression, and reduced ICD in the Fras1rdf hindlimb buds suggests that epithelium detachment from the mesenchyme may create a physical gap that interrupts the transmission of BMP, among other signals, resulting in soft tissue syndactyly.

Original languageEnglish (US)
Pages (from-to)497-507
Number of pages11
JournalDevelopmental Dynamics
Issue number4
StatePublished - Apr 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank Dr. Kathryn Anderson and her laboratory members, especially Dr. Joaquim Grego Bessa, for their guidance on setting up and conducting this ENU mutagenesis screen. We would like to thank Dr. Alex Shedlovsky and Dr. William F. Dove for their guidance on ENU mutagenesis, and Dr. Scott Weatherbee for his guidance on mapping and cloning of mutants. This work was supported by National Science Foundation Graduate Research Fellowship 2011101268 (to E.A.H), University of Wisconsin Genetics and SMPH funds for exploratory research, and the Romnes Faculty Fellowship from the University of Wisconsin Office of the Vice Chancellor for Research and Education, with funding from the Wisconsin Alumni Research Foundation (to X.S.).

Publisher Copyright:
© 2016 Wiley Periodicals, Inc.


  • BMP signaling
  • ENU screen
  • Fraser syndrome
  • Interdigital cell death
  • Limb development


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