title: 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.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Niedermaier
authors.forename: Georg C
authors.initials: GC
authors.lastname: Schwabe
authors.forename: Stephan
authors.initials: S
authors.lastname: Fees
authors.forename: Anne
authors.initials: A
authors.lastname: Helmrich
authors.forename: Norbert
authors.initials: N
authors.lastname: Brieske
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.forename: Volkhard
authors.initials: V
authors.lastname: Seitz
authors.forename: Sigmar
authors.initials: S
authors.lastname: Stricker
authors.forename: Gundula
authors.initials: G
authors.lastname: Leschik
authors.forename: Evelin
authors.initials: E
authors.lastname: Schrock
authors.forename: Paul B
authors.initials: PB
authors.lastname: Selby
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
mesh_terms: D000818:Animals; D007446:Chromosome Inversion; D002895:Chromosomes, Human, Pair 5; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005528:Foot / Q000033:anatomy & histology / Q000254:growth & development; D005532:Foot Deformities, Congenital; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006801:Humans; D017403:In Situ Hybridization; D007596:Joints / Q000033:anatomy & histology / Q000254:growth & development; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D010012:Osteogenesis / Q000502:physiology; D010641:Phenotype; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; C465570:Shh protein, mouse; D015534:Trans-Activators