title: Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh.
abstract: Sonic hedgehog (Shh) signaling regulates both digit number and identity, but how different distinct digit types (identities) are specified remains unclear. Shh regulates digit formation largely by preventing cleavage of the Gli3 transcription factor to a repressor form that shuts off expression of Shh target genes. The functionally redundant 5'Hoxd genes regulate digit pattern downstream of Shh and Gli3, through as yet unknown targets. Enforced expression of any of several 5'Hoxd genes causes polydactyly of different distinct digit types with posterior transformations in a Gli3(+) background, whereas, in Gli3 null limbs, polydactylous digits are all similar, short and dysmorphic, even though endogenous 5'Hoxd genes are broadly misexpressed. We show that Hoxd12 interacts genetically and physically with Gli3, and can convert the Gli3 repressor into an activator of Shh target genes. Several 5'Hoxd genes, expressed differentially across the limb bud, interact physically with Gli3. We propose that a varying [Gli3]:[total Hoxd] ratio across the limb bud leads to differential activation of Gli3 target genes and contributes to the regulation of digit pattern. The resulting altered balance between 'effective' Gli3 activating and repressing functions may also serve to extend the Shh activity gradient spatially or temporally.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Chen
authors.forename: Vladimir
authors.initials: V
authors.lastname: Knezevic
authors.forename: Valerie
authors.initials: V
authors.lastname: Ervin
authors.forename: Richard
authors.initials: R
authors.lastname: Hutson
authors.forename: Yvona
authors.initials: Y
authors.lastname: Ward
authors.forename: Susan
authors.initials: S
authors.lastname: Mackem
mesh_terms: D000818:Animals; D002417:Cattle; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009024:Morphogenesis; D009419:Nerve Tissue Proteins; D017689:Polydactyly / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D014034:Toes / Q000196:embryology*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection; D000074290:Zinc Finger Protein Gli3
chemical_list: D004268:DNA-Binding Proteins; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; C465570:Shh protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3