Characterization of neurite outgrowth and ectopic synaptogenesis in response to photoreceptor dysfunction
Characterization of neurite outgrowth and ectopic synaptogenesis in response to photoreceptor dysfunction
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DOI：
10.1007/s00018-012-1230-z
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发表时间：
2013-05-01
影响因子：
8
通讯作者：
Haverkamp, Silke
中科院分区：
文献类型：
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作者：
Michalakis, Stylianos;Schaeferhoff, Karin;Haverkamp, Silke
在哺乳动物视网膜中，光感受器产生的光信号通过突触接触传递到双极和水平细胞。在各种病理条件下，这些二级神经元将神经突延伸到外核层（ONL）。然而，与这种神经突生长相关的分子事件尚不清楚。在这里，我们描述了 CNGA3/CNGB1 双敲除 (A3B1) 小鼠（视网膜色素变性模型）的形态突触变化。在这些小鼠中，水平细胞在出生后第 11 天 (p) 之前看起来正常，但 1 天后开始在 ONL 中生长神经突。在第28页，发芽过程的数量减少，但剩余的芽在杆状细胞体处形成突触状接触，其超微结构外观让人想起带状突触。因此，A3B1 视网膜中的神经突生长和异位突触生成分别是从 p12 和 p28 开始的精确定时事件。因此，我们对这些年龄的 A3B1 和野生型小鼠的视网膜基因表达进行了微阵列分析，以评估这两个事件背后的基因组反应。该分析确定了 A3B1 视网膜中与神经突生长或突触可塑性相关的 163 个差异调节基因。 A3B1 视网膜基因表达的整体变化与 Tp53、Smad 和 Stat3 相关信号通路的激活一致。此外，这些信号传导途径的关键分子可能位于或靠近生长的神经突。因此，我们认为 Tp53、Smad 和 Stat3 信号通路有助于 A3B1 视网膜中的突触可塑性。
In the mammalian retina, light signals generated in photoreceptors are passed to bipolar and horizontal cells via synaptic contacts. In various pathological conditions, these second-order neurons extend neurites into the outer nuclear layer (ONL). However, the molecular events associated with this neurite outgrowth are not known. Here, we characterized the morphological synaptic changes in the CNGA3/CNGB1 double-knockout (A3B1) mouse, a model of retinitis pigmentosa. In these mice, horizontal cells looked normal until postnatal day (p) 11, but started growing neurites into the ONL 1 day later. At p28, the number of sprouting processes decreased, but the remaining sprouts developed synapse-like contacts at rod cell bodies, with an ultrastructural appearance reminiscent of ribbon synapses. Hence, neurite outgrowth and ectopic synaptogenesis in the A3B1 retina were precisely timed events starting at p12 and p28, respectively. We therefore performed microarray analysis of retinal gene expression in A3B1 and wild-type mice at those ages to evaluate the genomic response underlying these two events. This analysis identified 163 differentially regulated genes in the A3B1 retina related to neurite outgrowth or plasticity of synapses. The global changes in gene expression in the A3B1 retina were consistent with activation of signaling pathways related to Tp53, Smad, and Stat3. Moreover, key molecules of these signaling pathways could be localized at or in close proximity to outgrowing neurites. We therefore propose that Tp53, Smad, and Stat3 signaling pathways contribute to the synaptic plasticity in the A3B1 retina.