CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos.
CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos.
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DOI：
10.1111/joa.12712
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发表时间：
2018-04
影响因子：
2.4
通讯作者：
Vargesson N
中科院分区：
文献类型：
--
作者：
Mahony C;McMenemy S;Rafipay AJ;Beedie SL;Fraga LR;Gütschow M;Figg WD;Erskine L;Vargesson N
众所周知，沙利度胺会导致严重的出生缺陷，特别是四肢，在母亲使用该药治疗孕吐后，在子宫内暴露。这种药物是如何导致这些出生缺陷的尚不清楚。已经提出了许多理论，包括对正在形成的血管的作用。然而，沙利度胺幸存者也改变了神经模式，并且该药物因其长期使用后对成人的神经毒性作用而闻名。我们以前已经表明，CPS 49，沙利度胺的抗血管生成类似物，在鸡胚胎中以时间敏感的方式引起一系列肢体畸形。在这里，我们研究了CPS 49是否也是神经毒性的，以及对神经发育的影响是否会影响肢体发育。我们发现CPS 49是神经毒性的，就像沙利度胺一样，并且可以导致一些发育后期的鸡肢体神经元损失，但仅当肢体已经受到神经支配时。然而，当添加到后期发育的鸡肢中时，暴露于CPS 49不会导致肢尺寸的缺陷。相反，在未受神经支配的早期肢芽中，CPS 49暴露显著影响肢面积。为了更详细地研究神经毒性的作用及其对鸡肢体发育的影响，我们通过使用β-银环蛇毒素在一系列发育时间点抑制神经支配。我们发现，在肢体生长和神经支配之前、期间或之后，神经元抑制或消融不会导致明显的肢体软骨图案或数量变化。我们的结论是，虽然CPS 49是神经毒性的，考虑到发育肢体的晚期神经支配，并且在整个肢体发育过程中神经元抑制/消融不会引起与沙利度胺幸存者中所见相似的肢体图案异常，但神经缺陷不是CPS 49/沙利度胺诱导的严重肢体图案缺陷的主要根本原因。
Thalidomide notoriously caused severe birth defects, particularly to the limbs, in those exposed in utero following maternal use of the drug to treat morning sickness. How the drug caused these birth defects remains unclear. Many theories have been proposed including actions on the forming blood vessels. However, thalidomide survivors also have altered nerve patterns and the drug is known for its neurotoxic actions in adults following prolonged use. We have previously shown that CPS49, an anti-angiogenic analog of thalidomide, causes a range of limb malformations in a time-sensitive manner in chicken embryos. Here we investigated whether CPS49 also is neurotoxic and whether effects on nerve development impact upon limb development. We found that CPS49 is neurotoxic, just like thalidomide, and can cause some neuronal loss late developing chicken limbs, but only when the limb is already innervated. However, CPS49 exposure does not cause defects in limb size when added to late developing chicken limbs. In contrast, in early limb buds which are not innervated, CPS49 exposure affects limb area significantly. To investigate in more detail the role of neurotoxicity and its impact on chicken limb development we inhibited nerve innervation at a range of developmental timepoints through using β-bungarotoxin. We found that neuronal inhibition or ablation before, during or after limb outgrowth and innervation does not result in obvious limb cartilage patterning or number changes. We conclude that while CPS49 is neurotoxic, given the late innervation of the developing limb, and that neuronal inhibition/ablation throughout limb development does not cause similar limb patterning anomalies to those seen in thalidomide survivors, nerve defects are not the primary underlying cause of the severe limb patterning defects induced by CPS49/thalidomide.
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影响因子：
5.7
作者：
Beedie SL;Peer CJ;Pisle S;Gardner ER;Mahony C;Barnett S;Ambrozak A;Gütschow M;Chau CH;Vargesson N;Figg WD
通讯作者：
Figg WD
影响因子：
2.9
作者：
CHIAPPINELLI, VA;COHEN, JB;ZIGMOND, RE
通讯作者：
ZIGMOND, RE
DOI：
10.1073/pnas.1307684110
发表时间：
2013-07-30
影响因子：
11.1
作者：
Mahony, Chris;Erskine, Lynda;Vargesson, Neil
通讯作者：
Vargesson, Neil
影响因子：
2.8
作者：
DIETZ, FR
通讯作者：
DIETZ, FR
影响因子：
2.7
作者：
Harsum, S;Clarke, JDW;Martin, P
通讯作者：
Martin, P