Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb
Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb
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DOI：
10.1242/dev.037507
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发表时间：
2009-10-15
期刊：
影响因子：
4.6
通讯作者：
Wicking, Carol
中科院分区：
文献类型：
--
作者：
Butterfield, Natalie C.;Metzis, Vicki;Wicking, Carol
脊椎动物的刺猬受体patched 1（Ptc 1）是至关重要的负调节音刺猬（Shh）通路在前-后图案的肢体。我们有条件地灭活Ptc 1在小鼠肢体间充质中使用Prx 1-Cre。这导致在肢体出芽的早期阶段刺猬（Hh）信号传导的组成性激活。我们的数据表明，铬介导的切除的时间和效率的变化导致在不同的前肢和后肢表型。后肢显示多趾（获得的数字）和类似的Gli 3突变体外脚趾的分子概况。引人注目的是，前肢主要是寡趾（显示数字的损失），具有对称的镜像分子特征，这与前前肢到后前肢的重新指定一致。我们的数据表明，这是与非常早期失活的Ptc 1在前肢扰动的基因调控网络负责的预图案和随后的图案阶段的肢体发展。这些结果建立了Hh通路抑制的下游后果的重要性，并确定Ptc 1作为一个关键球员在肢体图案，甚至在发病前Shh表达。
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.