The acquisition of an opposable thumb is a crucial innovation in human evolution. Although this and other morphological differences in tetrapod fingers and toes reflect key functional adaptions, the molecular mechanisms that drive digit morphology are not well understood.
Researchers investigated the role of homeobox (Hox) gene expression on thumb formation by studying the limbs of the Hoxa13 mouse mutant, a line that lacks both the Hoxa13 gene and the thumb, also known as the number 1 digit.
The authors show that in Hoxa13 mutants, the expression of another Hox gene, Hoxd13, does not extend to the putative digit 1 region, thereby explaining why the digit fails to form.
Furthermore, this agenesis correlates with an increase in Gli3 repressor (Gli3R) activity due to the loss of the negative transcriptional regulation normally exerted by Hoxa13 and Hoxd13.
Initiation of Hoxd gene expression in the handplate depends on the sonic hedgehog (Shh) protein preventing Gli3R formation, and the study reveals the complex interactions between Hox genes and the Shh/Gli3 pathway.
According to the authors, Gli3 and Hox13 paralogs mutually antagonize each other to produce anterior–posterior asymmetry in the handplate and trigger thumb formation.
Genetic basis of thumb development in mice
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