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First published online September 25, 2009
doi: 10.1242/10.1242/dev.037507

Development 136, 3515-3524 (2009)
Published by The Company of Biologists 2009
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Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb

Natalie C. Butterfield1, Vicki Metzis1, Edwina McGlinn2, Stephen J. Bruce1, Brandon J. Wainwright1 and Carol Wicking1,*

1 The University of Queensland, Institute for Molecular Bioscience, Queensland 4072, Australia.
2 Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

* Author for correspondence (c.wicking{at}imb.uq.edu.au)

Accepted 21 August 2009

The vertebrate hedgehog receptor patched 1 (Ptc1) is crucial for negative regulation of the sonic hedgehog (Shh) pathway during anterior-posterior patterning of the limb. We have conditionally inactivated Ptc1 in the mesenchyme of the mouse limb using Prx1-Cre. This results in constitutive activation of hedgehog (Hh) signalling during the early stages of limb budding. Our data suggest that variations in the timing and efficiency of Cre-mediated excision result in differential forelimb and hindlimb phenotypes. Hindlimbs display polydactyly (gain of digits) and a molecular profile similar to the Gli3 mutant extra-toes. Strikingly, forelimbs are predominantly oligodactylous (displaying a loss of digits), with a symmetrical, mirror-image molecular profile that is consistent with re-specification of the anterior forelimb to a posterior identity. Our data suggest that this is related to very early inactivation of Ptc1 in the forelimb perturbing the gene regulatory networks responsible for both the pre-patterning and the subsequent patterning stages of limb development. These results establish the importance of the downstream consequences of Hh pathway repression, and identify Ptc1 as a key player in limb patterning even prior to the onset of Shh expression.

Key words: Patched 1, Sonic hedgehog signalling, Limb development, Prx1-Cre, Shh/Grem1/FGF loop, Mouse


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