Multiple roles of Hoxa11 and Hoxd11 in the formation of the mammalian forelimb zeugopod
2003
Mutations in the 5′ or posterior murine Hox genes (paralogous groups
9-13) markedly affect the formation of the stylopod, zeugopod and autopod of
both forelimbs and hindlimbs. Targeted disruption of Hoxa11 and
Hoxd11 or Hoxa10, Hoxc10 and Hoxd10 result in gross
mispatterning of the radius and ulna or the femur, respectively. Similarly, in
mice with disruptions of both Hoxa13 and Hoxd13 , development
of the forelimb and hindlimb autopod is severely curtailed. Although these
examples clearly illustrate the major roles played by the posterior Hox genes,
little is known regarding the stage or stages at which Hox transcription
factors intersect with the limb development program to ensure proper
patterning of the principle elements of the limb. Moreover, the cellular
and/or molecular bases for the developmental defects observed in these mutant
mice have not been described. In this study, we show that malformation of the
forelimb zeugopod in Hoxa11/Hoxd11 double mutants is a consequence of
interruption at multiple steps during the formation of the radius and ulna. In
particular, reductions in the levels of Fgf8 and Fgf10
expression may be related to the observed delay in forelimb bud outgrowth
that, in turn, leads to the formation of smaller mesenchymal condensations.
However, the most significant defect appears to be the failure to form normal
growth plates at the proximal and distal ends of the zeugopod bones. As a
consequence, growth and maturation of these bones is highly disorganized,
resulting in the creation of amorphous bony elements, rather than a normal
radius and ulna.
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