Molecular cloning and expression of the human and mouse homologues of the Drosophila dachshund gene

Abstract

Recent genetic analysis of the Drosophila dachshund (dac) gene has established that dac encodes a novel nuclear protein that is involved in both eye and leg development. In the Drosophila eye, dac expression appears to be controlled by the product of the eyeless/Pax6 gene. In order to analyze the Pax6 pathway in vertebrates we have isolated and characterized the cDNA and genomic clones corresponding to the human and mouse homologues of Drosophila dac. A full-length human cDNA encoding dachshund (DACH) encodes the 706 amino acids protein with predicted molecular weight of 73 kDa. A 109 amino acid domain located at the N-terminus of the DACH showed significant sequence and secondary structure homologies to the ski/sno oncogene products. Northern blot analysis found human DACH predominantly in adult kidney, heart, and placenta, with less expression detected in the brain, lung, skeletal muscle and pancreas. A panel of human cell lines was studied and most notably a large proportion of neuroblastomas expressed DACH mRNA. Mouse Dach encodes a protein of 751 amino acids with predicted molecular weight of 78 kDa that is 95% identical to the human DACH. RNase protection analysis showed the highest Dach mRNA expression in the adult mouse kidney and lung, whereas lower expression was detected in the brain and testis. RT/PCR analysis readily detected Dach mRNA in the adult mouse cornea and retina. Dach mRNA expression in the mouse E11.5 embryo was observed primarily in the fore and hind limbs, as well as in the somites.

Dach1 Mutant Mice Bear No Gross Abnormalities in Eye, Limb, and Brain Development and Exhibit Postnatal Lethality

“…Similarly, histological analysis of livers and liver-related functional tests, alanine aminotransferase and alkaline phosphatase, did not reveal any significant differences between wild-type and homozygous mutants (data not shown and Table 1). Dach1 expression has been detected in the kidneys, suggesting that the lethal/cyanotic phenotype may be related to an inability to regulate electrolyte concentrations and/or eliminate metabolic waste products (21). Histological analysis of the kidney did not reveal any structural defects between wild-type and mutant animals (data not shown).…”

“…Vertebrate homologues of eyeless (Pax6), eyes absent (Eya1 to Eya3), sine oculis (Six3 and Six6), and dachshund (Dach) that are expressed in the developing eye have been identified (3,4,10,11,15,20,21,29,31,37,41). Evidence of a functional role for some of these genes during eye development has also been demonstrated.…”

“…A mouse homologue of dachshund, Dach (hereafter referred to as Dach1), has been cloned, and its embryonic expression pattern has been characterized (4,11,15,21,25). Comparison of Dachshund and Dach1 sequences reveals the presence of two highly conserved sequences, Dachshund domain 1 (DD1) and DD2 (11).…”

Cell Fate Determination Factor DACH1 Inhibits c-Jun–induced Contact-independent Growth

“…Similarly, the c-fos promoter induction by serum was inhibited by DACH1 expression ( Figure 6F). DACH1 shares homology with Ski (Kozmik et al, 1999). To determine whether Ski functions as a transcriptional repressor of c-fos or c-jun promoter activity, serum induction experiments were conducted.…”

Targeted disruption of mouse Dach1 results in postnatal lethality

“…In mice, two dac homologues have been identified and transcripts are found during embryonic development in several areas, including the nervous system, retina, neural crest, limb buds, and genitalia (Hammond et al, 1998;Caubit et al, 1999;Davis et al, 1999Davis et al, , 2001bKozmik et al, 1999). The expression patterns of Dach1 and Dach2 are overlapping in limb buds, the telencephalon, the dorsal neural tube, and in the dermomyotome.…”