Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Royal Parade, Parkville, Victoria, Australia 3010
Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Royal Parade, Parkville, Victoria, Australia 3010.
J Neurosci. 2019 Aug 21;39(34):6656-6667. doi: 10.1523/JNEUROSCI.0278-19.2019. Epub 2019 Jul 12.
The growth of axons corresponding to different neuronal subtypes is governed by unique expression profiles of molecules on the growth cone. These molecules respond to extracellular cues either locally though cell adhesion interactions or over long distances through diffusible gradients. Here, we report that that the cell adhesion molecule ALCAM (CD166) can act as an extracellular substrate to selectively promote the growth of murine midbrain dopamine (mDA) neuron axons through a -heterophilic interaction with mDA-bound adhesion molecules. In mixed-sex primary midbrain cultures, the growth-promoting effect of ALCAM was abolished by neutralizing antibodies for components of the Semaphorin receptor complex Nrp1, Chl1, or L1cam. The ALCAM substrate was also found to modulate the response of mDA neurites to soluble semaphorins in a context-specific manner by abolishing the growth-promoting effect of Sema3A but inducing a branching response in the presence of Sema3C. These findings identify a previously unrecognized guidance mechanism whereby cell adhesion molecules act in to modulate the response of axonal growth cones to soluble gradients to selectively orchestrate the growth and guidance of mDA neurons. The mechanisms governing the axonal connectivity of midbrain dopamine (mDA) neurons during neural development have remained rather poorly understood relative to other model systems for axonal growth and guidance. Here, we report a series of novel interactions between proteins previously not identified in the context of mDA neuronal growth. Significantly, the results suggest a previously unrecognized mechanism involving the convergence in signaling between local, adhesion and long-distance, soluble cues. A better understanding of the molecules and mechanisms involved in establishment of the mDA system is important as a part of ongoing efforts to understand the consequence of conditions that may result from aberrant connectivity and also for cell replacement strategies for Parkinson's disease.
轴突的生长对应于不同神经元亚型，由生长锥上分子的独特表达谱决定。这些分子通过细胞粘附相互作用在局部或通过可扩散的梯度在长距离内对细胞外线索做出反应。在这里，我们报告细胞粘附分子 ALCAM（CD166）可以作为细胞外基质，通过与结合在 mDA 神经元上的粘附分子的异亲性相互作用，选择性地促进小鼠中脑多巴胺（mDA）神经元轴突的生长。在混合性别原代中脑培养物中，中和抗体可消除 ALCAM 对 Semaphorin 受体复合物 Nrp1、Chl1 或 L1cam 成分的生长促进作用。还发现 ALCAM 基质以特定于上下文的方式调节 mDA 突起对可溶性信号素的反应，通过消除 Sema3A 的生长促进作用，但在存在 Sema3C 的情况下诱导分支反应。这些发现确定了一种以前未被识别的制导机制，即细胞粘附分子在局部和远距离可溶性梯度之间的信号转导中发挥作用，以选择性地协调 mDA 神经元的生长和导向。与其他用于轴突生长和导向的模型系统相比，中脑多巴胺（mDA）神经元在神经发育过程中的轴突连接机制仍然知之甚少。在这里，我们报告了一系列以前在 mDA 神经元生长背景下未被识别的蛋白之间的新相互作用。重要的是，这些结果表明了一种以前未被认识到的机制，涉及局部、粘附和远距离、可溶性线索之间信号转导的收敛。更好地了解参与 mDA 系统建立的分子和机制很重要，因为这是了解可能由于异常连接导致的条件的后果以及帕金森病的细胞替代策略的一部分。
