A novel member of the F-box/WD40 gene family, encoding dactylin, is disrupted in the mouse dactylaplasia mutant

Abstract

Early outgrowth of the vertebrate embryonic limb requires signalling by the apical ectodermal ridge (AER) to the progress zone (PZ), which in response proliferates and lays down the pattern of the presumptive limb in a proximal to distal progression. Signals from the PZ maintain the AER until the anlagen for the distal phalanges have been formed. The semidominant mouse mutant dactylaplasia (Dac) disrupts the maintenance of the AER, leading to truncation of distal structures of the developing footplate, or autopod. Adult Dac homozygotes thus lack hands and feet except for malformed single digits, whereas heterozygotes lack phalanges of the three middle digits. Dac resembles the human autosomal dominant split hand/foot malformation (SHFM) diseases. One of these, SHFM3, maps to chromosome 10q24 (Refs 6,7), which is syntenic to the Dac region on chromosome 19, and may disrupt the orthologue of Dac. We report here the positional cloning of Dac and show that it belongs to the F-box/WD40 gene family, which encodes adapters that target specific proteins for destruction by presenting them to the ubiquitination machinery. In conjuction with recent biochemical studies, this report demonstrates the importance of this gene family in vertebrate embryonic development.

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

“…While a nonheritable or disruptive cause could potentially cause atypical SHFM, the marked clinical variability of SHFM usually makes it difficult to completely exclude a genetic/heritable cause. SHFM is not exclusively observed in humans, having been described in other species such as chicken, frogs, and mice [Sidow et al, 1999], indicating a common developmental pathway that is highly conserved throughout evolution [Gurrieri et al, 2002].…”

“…, which were originally characterized as rearrangements of the Dactylin (Dac) gene, now called Fbxw4 [Sidow et al, 1999]. Further studies demonstrated that both mutations consist of insertions of a virtually identical LTR retrotransposon sequence (a MusD element), located upstream of the promoter in Dac 1J and within intron 5 in Dac 2J [Kano et al, 2007;Friedli et al, 2008].…”

“…Studies of the Dac mouse have been critical to the investigation of the SHFM3 locus [Chai, 1981;Johnson et al, 1995;Seto et al, 1997;Crackower et al, 1998;Sidow et al, 1999]. The Dac phenotype is caused by digenic inheritance, manifesting only in the presence of a heterozygous or homozygous mutation at the primary causative locus, Dac, in combination with homozygosity at a secondary (permissive or modifier) locus, known as the modifier of Dac, or mdac.…”

“…Further studies demonstrated that both mutations consist of insertions of a virtually identical LTR retrotransposon sequence (a MusD element), located upstream of the promoter in Dac 1J and within intron 5 in Dac 2J [Kano et al, 2007;Friedli et al, 2008]. Fbxw4 is a member of the F-box WD-40 gene family, whose members encode subunits of ubiquitin ligases that present phosphorylated protein targets to ubiquitin-containing enzymes for degradation, and the protein is thought to function in maintaining the AER of the developing limb bud [Johnson et al, 1995;Seto et al, 1997;Crackower et al, 1998;Sidow et al, 1999]. However, it is not clear whether Fbxw4 itself is the primary cause of the Dac phenotype.…”

Genetically regulated epigenetic transcriptional activation of retrotransposon insertion confers mouse dactylaplasia phenotype

“…Two independent Dac mutant alleles, Dac 1J and Dac 2J , arose spontaneously in breeding colonies. Both are insertions residing within the same locus: Dac 1J is located in the region upstream of the dactylin gene, and Dac 2J is located in intron 5 of dactylin (3). Southern blot analysis indicated that both insertions are larger than 4.5 kb; however, ''jumping PCR'' identified only the LTR portion of the insertion (3).…”