Recent studies show that Hox homeodomain proteins from paralog groups 1 to 10 gain DNA binding specificity and affinity through cooperative binding with the divergent homeodomain protein Pbx1. However, the AbdB-like Hox proteins from paralogs 11, 12, and 13 do not interact with Pbx1a, raising the possibility of different protein partners. The Meis1 homeobox gene has 44% identity to Pbx within the homeodomain and was identified as a common site of viral integration in myeloid leukemias arising in BXH-2 mice. These integrations result in constitutive activation of Meis1. Furthermore, the Hoxa-9 gene is frequently activated by viral integration in the same BXH-2 leukemias, suggesting a biological synergy between these two distinct classes of homeodomain proteins in causing malignant transformation. We now show that the Hoxa-9 protein physically Although the vertebrate homeobox genes play a critical role in embryonic development (30), there has been little progress in understanding how homeodomain proteins function. Despite the assumption that they are transcription factors (24), few natural regulatory targets have been identified (13, 16), and little data exist showing an in vivo transcriptional role for the mammalian homeodomain proteins. Vertebrate homeobox genes can be divided into the Hox family of clustered genes which contain homeobox sequences related to the Drosophila HOM-C homeobox genes and the numerous subfamilies of non-Hox genes which possess more distantly related homeobox sequences. The 39 Hox genes are arranged in four separate loci (A, B, C, and D), and the genes in different clusters can be aligned on the basis of homology within the homeobox to form so-called paralog groups, which have limited homology with the Drosophila HOM-C genes as well (1). A significant advance in understanding how Hox proteins function has been the demonstration that they form cooperative DNA binding complexes with the non-Hox homeodomain protein Pbx1a (10, 27, 42). We have recently reported that Hox proteins from paralog groups 1 through 10 gain DNA binding specificity through cooperative binding with Pbx1a, but proteins from the remaining three paralog groups, 11, 12, and 13, do not appear to interact with Pbx1a (8, 47). These findings suggest that the Hox proteins from paralog groups 11 through 13 might cooperatively bind to DNA with other non-Hox homeodomain protein partners.In recent studies, we demonstrated that a novel homeobox gene, Meis1, is a common site of viral integration in myeloid leukemias occurring in BXH-2 mice (33). Two forms of the Meis1 transcript, which differ in the amino acid sequence Cterminal to the homeodomain, were identified in all tissues examined (33). The homeodomain of Meis1 has homology with that of Pbx1, and both proteins contain a 3-amino-acid insertion which is a feature of the TALE class of homeobox genes (2). With the exception of the recently described Meisrelated genes (34,48), the N-terminal and C-terminal flanking regions of Meis1 have no homology to known homeodomain proteins. A...

The Pleisl locus was isolated as a common site of viral integration involved in myeloid leukemia in BXH-2 mice. Meisl encodes a novel homeobox protein belonging to the TALE (three amino acid loop extension) family of homeodomain-containing proteins. The homeodomain of Meisl is the only known motif within the entire 3?O-amino-acid protein. Southern blot analyses using the Meisl homeodomain as a probe revealed the existence of a family of Meisl-related genes (Mrgs) in several diverged species, in addition, the 3' untranslated region (UTR) of Meisl was remarkably conserved in evolution. To gain a further understanding of the role lqeisl plays in leukemia and development, as well as to identify conserved regions of the protein that might reveal function, we cloned and characterized lqrgs from the mouse and human genomes. We report the sequence of Mrgl and IqR62 as well as their chromosomal locations in murine and human genomes. Both Plrgs share a high degree of sequence identity with the protein coding region of Meisl. We have also cloned the Xenopus laevis ortholog of Meisl (XMeisl). Sequence comparison of the murine and Xenopus clones reveals that lqeisl is highly conserved throughout its coding sequence as well as the 3' UTR. Finally, comparison of Meisl and the closely related Mrgs to known homeoproteins suggests that lqeisl represents a new subfamily of TALE homeobox genes.

In the course of studying the genetics of chlorambucil mutagenesis, we have uncovered a new model for autosomal polycystic kidney disease (PKD). In the homozygous condition, the gene, jcpk, causes a very severe disease characterized by cysts in all segments of the nephron. Death usually occurs before 10 days of age. Extrarenal involvement was also noted; enlarged bile ducts, pancreatic ducts, and gall bladder often accompanied the PKD. In addition, approximately 25% of the aged +/jcpk heterozygotes show evidence of glomerulocystic disease. This gene maps to Chromosome 10 between two DNA markers, D10Mit20 and D10Mit42. Because this gene causes extrarenal abnormalities and because it has a heterozygote effect, it may be an informative animal model for the commonly occurring human adult dominant PKD.

Six carbonic anhydrase (CA) isozymes (CA I-VI) in mammals and other amniotes have been described. We have isolated an additional CA gene from a human genomic library and designated its putative product carbonic anhydrase VII (CA VII). The gene is approximately 10 kb long and contains seven exons and six introns found at positions identical to those determined for the previously described CA I, CA II, and CA III genes. The finding of a 17-bp GT-rich segment in a position 28 bp downstream of the poly(A)+ signal and the high correspondence of the 5' and 3' splice sites of the six introns with consensus junction sequences are consistent with the gene being functional. The 5' flanking regions of the CA VII gene do not contain the TATA and CAAT promoter elements usually found within 100 bp upstream of transcription initiation, but do contain a TTTAA sequence 102 nucleotides upstream of the initiation codon. The 5' region of the gene (-243 to +551) is GC-rich and contains 80 CpG dinucleotides and four possible Sp1 (GGGCGG or CCGCCC) binding sites. Northern analysis has identified the salivary gland as a major site of expression. The derived amino acid sequence of the CA VII gene is 263 amino acids long and has 50, 56, and 49% identity with human CA I, CA II, and CA III, respectively. No differences were found at any of the 39 positions that have remained invariant in all mammalian CA isozymes sequenced to date. Based on analysis of interspecific somatic cell hybrids, the human CA VII gene, CA7, was assigned to chromosome 16, with localization to the long arm at the q21-23 region by in situ hybridization. This is in contrast to the location of the CA I, CA II, and CA III gene cluster on human chromosome 8 and that of the human CA VI gene on chromosome 1.