An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression
Michael Niedermaier, … , Paul B. Selby, Stefan Mundlos
Michael Niedermaier, … , Paul B. Selby, Stefan Mundlos
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):900-909. https://doi.org/10.1172/JCI23675.
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Article Bone biology

An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression

Abstract

Short digits (Dsh) is a radiation-induced mouse mutant. Homozygous mice are characterized by multiple defects strongly resembling those resulting from Sonic hedgehog (Shh) inactivation. Heterozygous mice show a limb reduction phenotype with fusion and shortening of the proximal and middle phalanges in all digits, similar to human brachydactyly type A1, a condition caused by mutations in Indian hedgehog (IHH). We mapped Dsh to chromosome 5 in a region containing Shh and were able to demonstrate an inversion comprising 11.7 Mb. The distal breakpoint is 13.298 kb upstream of Shh, separating the coding sequence from several putative regulatory elements identified by interspecies comparison. The inversion results in almost complete downregulation of Shh expression during E9.5–E12.5, explaining the homozygous phenotype. At E13.5 and E14.5, however, Shh is upregulated in the phalangeal anlagen of Dsh/+ mice, at a time point and in a region where WT Shh is never expressed. The dysregulation of Shh expression causes the local upregulation of hedgehog target genes such as Gli1-3, patched, and Pthlh, as well as the downregulation of Ihh and Gdf5. This results in shortening of the digits through an arrest of chondrocyte differentiation and the disruption of joint development.

Authors

Michael Niedermaier, Georg C. Schwabe, Stephan Fees, Anne Helmrich, Norbert Brieske, Petra Seemann, Jochen Hecht, Volkhard Seitz, Sigmar Stricker, Gundula Leschik, Evelin Schrock, Paul B. Selby, Stefan Mundlos

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Figure 7

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Digit development and joint formation. Schematic of WT (left) and Dsh/+ ...
Digit development and joint formation. Schematic of WT (left) and Dsh/+ (right) digit and joint development and gene expression patterns corresponding to E12.5 (top), E13.5 (middle), and E14.5 (bottom). The expression domains of Ihh, Pthlh, Gdf5, and Shh are indicated. Ihh induces Pthlh at a distance and thereby regulates the distance to the developing joint space (arrows). Gdf5 is first expressed around the condensing cells of the cartilaginous anlage (E12.5) and then in the future joint space, where it regulates cell recruitment and proliferation. In Dsh/+ limbs, this process is disrupted after E13 by expression of Shh in the cartilaginous anlagen and the perichondrium of the future P1, thereby inducing Pthlh and repressing Ihh and Gdf5. In contrast, Shh is not expressed in the metacarpals. This results in a fusion of P1 and P2, an impediment in the formation of the metacarpophalangeal joint, and a delayed chondrocyte differentiation and bone formation in the metacarpals.