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First published online 21 April 2004
doi: 10.1242/dev.01115
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1 Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD
20892, USA
2 Cell and Cancer Biology Branch, Center for Cancer Research, NCI, NIH,
Bethesda, MD 20892, USA
Author for correspondence (e-mail:
smack{at}helix.nih.gov)
Accepted 9 February 2004
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.
Key words: AP pattern, Digit formation, Limb development, Hoxd genes, Gli3, Sonic hedgehog, Mouse
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