BMP-2 functions independently of SHH signaling and triggers cell condensation and apoptosis in regenerating axolotl limbs.
BMP-2 functions independently of SHH signaling and triggers cell condensation and apoptosis in regenerating axolotl limbs.
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DOI：
10.1186/1471-213x-10-15
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发表时间：
2010-02-12
影响因子：
--
通讯作者：
Roy S
中科院分区：
文献类型：
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作者：
Guimond JC;Lévesque M;Michaud PL;Berdugo J;Finnson K;Philip A;Roy S
在脊椎动物中，蝾螈具有独特的能力，可以在截肢后完美地再生复杂的身体部位，如四肢。此外，蝾螈的模式发展和再生的autopods从前面到后面的轴，而不是像所有的四足动物研究到目前为止，从后面到前面。音速刺猬在所有四足动物包括蝾螈的四肢前后轴的建立中非常重要。有趣的是，它的表达是保守的（肢芽和芽基的后侧）在蝾螈四肢在其他四足动物。已经提出BMP-2可能是音刺猬的次要介质，尽管在小鼠中有越来越多的相反证据。由于BMP-2的表达是在发展和再生肢体的前部数字图案化之前，相反的表达的音刺猬，我们研究了BMP-2的表达是否依赖于音刺猬信号，以及它是否影响图案化的autopod在再生过程中。BMP-2和SOX-9在发育和再生的蝾螈肢体中的表达对应于第一趾在足类的前部形成。用环巴胺抑制音刺猬信号传导导致了发育不全的肢体（在发育和再生过程中），但不影响BMP-2和SOX-9的表达。BMP-2在再生肢体中的过度表达导致了手指的缺失。再生肢体中Noggin（BMP抑制剂）的过度表达也导致了手指的缺失。组织学分析表明，由于BMP-2过表达的损失是增加的细胞凝聚和凋亡的结果，而由Noggin引起的损失是由于细胞分裂减少。BMP-2及其靶SOX-9的表达在发育和再生肢体中不依赖于音刺猬信号。它们的表达与软骨形成和骨骼元素的外观相关，在其他四足动物中也有描述。BMP-2的过表达并没有引起多余指的形成，这与它不是音刺猬的次级信号的假设一致。然而，它确实导致了由于细胞凝聚和凋亡增加而形成的亚形肢。综上所述，这些结果表明，BMP-2没有直接的作用，在图案再生肢体，但可能是重要的，以触发冷凝前骨化和介导细胞凋亡。
Axolotls have the unique ability, among vertebrates, to perfectly regenerate complex body parts, such as limbs, after amputation. In addition, axolotls pattern developing and regenerating autopods from the anterior to posterior axis instead of posterior to anterior like all tetrapods studied to date. Sonic hedgehog is important in establishing this anterior-posterior axis of limbs in all tetrapods including axolotls. Interestingly, its expression is conserved (to the posterior side of limb buds and blastemas) in axolotl limbs as in other tetrapods. It has been suggested that BMP-2 may be the secondary mediator of sonic hedgehog, although there is mounting evidence to the contrary in mice. Since BMP-2 expression is on the anterior portion of developing and regenerating limbs prior to digit patterning, opposite to the expression of sonic hedgehog, we examined whether BMP-2 expression was dependent on sonic hedgehog signaling and whether it affects patterning of the autopod during regeneration. The expression of BMP-2 and SOX-9 in developing and regenerating axolotl limbs corresponded to the first digits forming in the anterior portion of the autopods. The inhibition of sonic hedgehog signaling with cyclopamine caused hypomorphic limbs (during development and regeneration) but did not affect the expression of BMP-2 and SOX-9. Overexpression of BMP-2 in regenerating limbs caused a loss of digits. Overexpression of Noggin (BMP inhibitor) in regenerating limbs also resulted in a loss of digits. Histological analysis indicated that the loss due to BMP-2 overexpression was the result of increased cell condensation and apoptosis while the loss caused by Noggin was due to a decrease in cell division. The expression of BMP-2 and its target SOX-9 was independent of sonic hedgehog signaling in developing and regenerating limbs. Their expression correlated with chondrogenesis and the appearance of skeletal elements has described in other tetrapods. Overexpression of BMP-2 did not cause the formation of extra digits, which is consistent with the hypothesis that it is not the secondary signal of sonic hedgehog. However, it did cause the formation of hypomorphic limbs as a result of increased cellular condensation and apoptosis. Taken together, these results suggest that BMP-2 does not have a direct role in patterning regenerating limbs but may be important to trigger condensation prior to ossification and to mediate apoptosis.