Distinct functions of homeodomain-containing and homeodomain-less isoforms encoded by homothorax.
The homothorax (hth) gene of Drosophila melanogaster is required for executing Hox functions, for head development, and for forming the proximodistal (PD) axis of the appendages. We show that alternative splicing of hth generates two types of protein isoforms, one that contains a DNA-binding homeodomain (HthFL) and one that does not contain a homeodomain (HDless). Both types of Hth isoforms include the evolutionarily conserved HM domain, which mediates a direct interaction with Extradenticle (Exd), another homeodomain protein. We show that although both HthFL and HDless isoforms of Hth can induce the nuclear localization of Exd, they carry out distinct sets of functions during development. Surprisingly, we find that many of hth's functions, including PD patterning and most Hox-related activities, can be executed by the HDless isoforms. In contrast, antennal development shows an absolute dependency on the HthFL isoform. Thus, alternative splicing of hth results in the generation of multiple transcription factors that execute unique functions in vivo. We further demonstrate that the mouse ortholog of hth, Meis1, also encodes a HDless isoform, suggesting that homeodomain-less variants of this gene family are evolutionarily ancient.
Noro
Barbara
B
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
Culi
Joaquim
J
McKay
Daniel J
DJ
Zhang
Wen
W
Mann
Richard S
RS
D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000825:Animal Structures / Q000033:anatomy & histology / Q000196:embryology; D000818:Animals; D019521:Body Patterning; D004247:DNA / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006257:Head / Q000196:embryology; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010641:Phenotype; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; C083405:exd protein, Drosophila; C108704:hth protein, Drosophila; D004247:DNA