Department of Neuroscience and Neuroscience Training Program, University of Wisconsin, Madison, WI 53706, USA.
Department of Neuroscience and Neuroscience Training Program, University of Wisconsin, Madison, WI 53706, USA
Development. 2015 Feb 1;142(3):486-96. doi: 10.1242/dev.108266. Epub 2015 Jan 6.
Invadopodia and podosomes, collectively referred to as invadosomes, are F-actin-rich basal protrusions of cells that provide sites of attachment to and degradation of the extracellular matrix. Invadosomes promote the invasion of cells, ranging from metastatic cancer cells to immune cells, into tissue. Here, we show that neuronal growth cones form protrusions that share molecular, structural and functional characteristics of invadosomes. Growth cones from all neuron types and species examined, including a variety of human neurons, form invadosomes both in vitro and in vivo. Growth cone invadosomes contain dynamic F-actin and several actin regulatory proteins, as well as Tks5 and matrix metalloproteinases, which locally degrade the matrix. When viewed using three-dimensional super-resolution microscopy, F-actin foci often extended together with microtubules within orthogonal protrusions emanating from the growth cone central domain. Finally, inhibiting the function of Tks5 both reduced matrix degradation in vitro and disrupted motoneuron axons from exiting the spinal cord and extending into the periphery. Taken together, our results suggest that growth cones use invadosomes to target protease activity during axon guidance through tissues.
侵袭伪足和足突，统称为侵袭小体，是富含 F-肌动蛋白的细胞基底突起，为细胞附着和细胞外基质降解提供了部位。侵袭小体促进了从转移性癌细胞到免疫细胞等各种细胞向组织的侵袭。在这里，我们表明神经元生长锥形成的突起具有侵袭小体的分子、结构和功能特征。我们研究了所有类型和物种的神经元，包括多种人类神经元，发现它们在体外和体内都能形成侵袭小体。生长锥侵袭小体包含动态 F-肌动蛋白和几种肌动蛋白调节蛋白，以及 Tks5 和基质金属蛋白酶，它们局部降解基质。当使用三维超分辨率显微镜观察时，F-肌动蛋白焦点经常与从生长锥中央区域发出的正交突起内的微管一起延伸。最后，抑制 Tks5 的功能不仅减少了体外基质的降解，还破坏了运动神经元轴突从脊髓中退出并延伸到外围的过程。总之，我们的研究结果表明，生长锥在通过组织进行轴突导向时，利用侵袭小体来靶向蛋白酶活性。
