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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

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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 4

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The Dsh/+ limb phenotype. (A) Alizarin red–stained skeletal preparations...
The Dsh/+ limb phenotype. (A) Alizarin red–stained skeletal preparations of 4-week-old WT and Dsh/+ forelimb digits. MC, metacarpals. Digits I–V are shown. In Dsh/+ mice, the P1 and P2 elements are fused (P1/2, arrows) and severely reduced in size. In digit IV, the metacarpo-phalangeal joint is also fused. MC, metacarpals. (B) Hindlimb of WT and Dsh/+ adult mouse showing severe reduction in digit length. (C) Alcian blue staining of E15.5 WT and Dsh/+ limbs. Note lack of the middle phalanx anlage in all digits and persistent staining between the developing metacarpal and P1, indicating delayed or absent joint formation (arrow). (D) H&:E staining of E14.5 WT and Dsh/+ digits. WT shows the beginning of joint formation (arrow). In contrast, Dsh/+ shows lack of joint interzone formation and undifferentiated chondrocytes in the region of prospective phalanges (arrow). (E) BrdU staining of E14.5 WT and Dsh/+ autopod (top) and digits (bottom) showing reduced proliferation in the region of joint formation (arrows). (F) TUNEL staining showing lack of apoptosis in joint interzones (arrow). Magnification, ×18 (A), ×7 (B), ×40 (C), ×50 (E), ×100 (D and F).

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