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.
Highlights
Digits arise as single chondrogenic condensations that later segment and grow differentially to acquire defining features, such as the number, size and shape of their phalanges (Dahn and Fallon, 2000)
We previously showed that a Hoxd12 transgene (Tg-Hoxd12), expressed throughout the limb bud, causes polydactyly and ectopic anterior Sonic hedgehog (Shh) expression (Knezevic et al, 1997). 5′Hoxd genes are downstream targets of Gli3, and their expression is broadly activated across the early limb bud in Gli3–/– embryos (Zuniga and Zeller, 1999)
To investigate the possible basis for phenotypic similarities and differences resulting from Hoxd gain of function versus Gli3 loss of function, we analyzed progeny from crosses between Gli3+/– and Tg-Hoxd12 mice using a weakly expressing TgHoxd12 line (Knezevic et al, 1997) that, when hemizygous, has no abnormal phenotype alone (Fig. 1A)
Summary
Digits arise as single chondrogenic condensations that later segment and grow differentially to acquire defining features, such as the number, size and shape of their phalanges (segments) (Dahn and Fallon, 2000) (see reviews by Mariani and Martin, 2003; Tickle, 2003). The pattern of different digits (I to V) that form from anterior (A; digit I, e.g. thumb) to posterior (P; digit V, e.g. little finger) is controlled by secreted Shh signals produced in the posterior limb bud mesoderm (reviewed by Ingham and McMahon, 2001; Mariani and Martin, 2003; Tickle, 2003). Shh regulates both digit number and identity in a dose-dependent manner; increasing levels of Shh expand digit-forming capacity and specify more posterior digit identities (Yang et al, 1997; Lewis et al, 2001). In addition to functioning antagonistically, Gli represses Shh expression and, in
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