Saturday, September 25, 2010

Evolution of tetrapod limbs

Partial deletions of HOX genes were done on mutant mice to understand the control they have on Sonic Hedgehog (Shh) expression.  It was already understood that Shh determined the anterior-to-posterior polarity of tetrapod limbs.  But this study (by Tarchini, Duboule, and Kmita,  published in Nature) showed that deleting a certain range of HOX genes inhibited Shh expression, which kept limbs from properly forming or sometimes from even forming at all.  

Figure 3: Skeletons in the presence or absence of Shh signaling.

Shh transcription was absent altogether when all Hoxa and Hoxd8 through Hoxd13 genes were deleted.  Interestingly, Shh transcription still did not take place even though Hoxd1, Hoxd3, and Hoxd4 were present, suggesting those genes are unable to trigger Shh transcription.  Adding both Hoxd8 and Hoxd9 did not cause Shh transcription.  Deleting Hoxd10 and Hoxd13 led to upregulation of Hoxd9, but that did not lead to Shh expression.  Addition of Hoxd13 alone induced the formation of both digits and a remnant of forearm.  Hoxd10 function induced a clear yet truncated forearm followed by a series of rays (see Figure 3a above).

Figure 1: Control of Shh expression by Hoxa and Hoxd genes.

This study reinforced that in order for tetrapod limbs to form correctly, the correct HOX genes must be activated (by Shh) in the correct order.  Tarchini, Duboule, and Kmita suggest that tetrapod limbs evolved along with the recruitment of the Hox mechanism implemented in the developing body axis.

Citation: Nature 443, 985-988 (26 October 2006); Received 14 July 2006; Accepted 15 September 2006


  1. Nice data showing the link between HOX genes, Shh and limb growth, and very timely as we move onto tetrapod evolution next week. You mention that Shh is activating HOX genes as well, and not just the other way around. Is this correct?

  2. I just re-read the paper, and it isn't correct - the HOX genes induce transcription of Shh, but Shh doesn't activate HOX genes. That was a paraphrasing error on my part.
    What I was trying to say was that in order for tetrapod limbs to form correctly by Shh, the correct HOX genes must be activated in the correct order, which is anterior to posterior. If the select HOX genes they mention are skipped, or if the activation order is wrong, the limbs will form incorrectly.

  3. Thanks for the clarification. Neat paper and good summary.

  4. Very interesting. So it is not only which hox genes are activated but in specific order too? Wow!