Drosophila spalt/spalt-related mutants exhibit Townes-Brocks' syndrome phenotypes

Abstract

Mutations in SALL1, the human homolog of the Drosophila spalt gene, result in Townes-Brocks' syndrome, which is characterized by hand͞foot, anogenital, renal, and ear anomalies, including sensorineural deafness. spalt genes encode zinc finger transcription factors that are found in animals as diverse as worms, insects, and vertebrates. Here, we examine the effect of losing both of the spalt genes, spalt and spalt-related, in the fruit fly Drosophila melanogaster, and report defects similar to those in humans with Townes-Brocks' syndrome. Loss of both spalt and spalt-related function in flies yields morphological defects in the testes, genitalia, and the antenna. Furthermore, spalt͞spalt-related mutant antennae show severe reductions in Johnston's organ, the major auditory organ in Drosophila. Electrophysiological analyses confirm that spalt͞spalt-related mutant flies are deaf. These commonalities suggest that there is functional conservation for spalt genes between vertebrates and insects.Distal-less ͉ homothorax ͉ atonal ͉ chordotonal organ ͉ split hand͞split foot malformation T ownes-Brocks' syndrome (TBS) is an autosomal dominant disorder that maps to the SALL1 locus at 16q12.1 (1). SALL1 is one of three known vertebrate homologs of Drosophila spalt (sal) (2, 3). The mutations in SALL1 that result in TBS typically lead to a premature stop codon after the first zinc finger (1, 4-7). Although the clinical manifestations of TBS are variable, Ϸ85% of patients with TBS exhibit hand͞foot, anogenital, renal, and ear anomalies, including sensorineural deafness (8-13). TBS is estimated to occur in 1:250,000 liveborn (14), but may be misdiagnosed because its defects overlap with those of other genetic diseases (7,11,15,16). Consistent with TBS phenotypes, human SALL1 expression has been detected in the brain, heart, ureteric bud, and developing tubules of the kidney, testes, and ovary (2, 17). In mice, sal genes are expressed in brain, testes, ovaries, kidneys, limb buds, heart, inner ear, and the lens of the eye (18,19).spalt genes have been identified in a variety of vertebrates and invertebrates (2,3,18,(20)(21)(22)(23)(24)(25)(26)(27)(28). In Drosophila, there are two adjacent spalt genes, spalt (sal) and spalt-related (salr). These genes use shared regulatory regions and are expressed in similar patterns throughout development. Early studies of sal single mutants indicated that sal is required for the development of the embryonic terminalia, tracheal system, and wings (20,(29)(30)(31)(32). Mutations in sal result in partial transformations of the posterior head and anterior tail toward trunk identity (20). sal functions during tracheal development both to restrict the positions of the initial placodes and in directed migration of dorsal trunk cells (30). At larval stages, Dpp-activated sal expression in the wing pouch is activated in response to graded levels of Dpp to properly position wing pattern elements (29,31,33).More recent studies of Drosophila lacking the function of both sal and salr indicate that there ...

The female-specific Doublesex isoform regulates pleiotropic transcription factors to pattern genital development inDrosophila

“…Five loci were previously shown to be expressed sexdifferentially in L3 genital discs. Of these, all five were significantly differentially expressed in our analysis at a stringent FDR threshold of 0.05: bnl and btl ; abdominal A (abd-A) (Freeland and Kuhn, 1996;Casares et al, 1997;Chen et al, 2005); Wnt oncogene analog 2 (Wnt2) (Kozopas et al, 1998); and the paralogous, adjacent spalt (sal) genes (Dong et al, 2003). Additional significant loci can be considered positive controls as well, although their expression in genital discs had not been quantified directly: the female-specific dsx isoform; malespecific lethal 2 (msl-2), which shows lower mRNA levels in whole females than males (Bashaw and Baker, 1997); bab1/2, the protein expression of which in L3 discs appears different in males and females but had not been quantified (Couderc et al, 2002); Pox neuro (Poxn), which was shown to be expressed in male discs at time points later than ours (Boll and Noll, 2002); and stumps, which appears upregulated in btl-expressing cells as they transition to epithelium and which shows, consistent with this observation, significantly male-biased expression at P6 and P20 but not L3.…”

Mechanotransduction and auditory transduction in Drosophila

“…The stalk and socket walls are stiffened so that all movement is translated into a rocking of the ring-joint on its vertical axis [37]. Formation of this specialized organ from epidermal cells requires the redundant zinc-finger proteins encoded by spalt (sal) and spaltrelated (salr): sal salr double mutants have fused segments and disorganized scolopidia and are completely deaf [23].…”

Differential expression of the novel oncogene, SALL4, in lymphoma, plasma cell myeloma, and acute lymphoblastic leukemia

“…[15][16][17][18][19] Human SALL4 mutations are associated with Duane radial ray syndrome (or Okihiro syndrome). 3,[20][21][22] Duane radial ray syndrome is a human autosomal-dominant syndrome involving radialsided hand anomalies in association with Duane syndrome.…”