Complement component C3aR constitutes a novel regulator for chick eye morphogenesis.
Complement component C3aR constitutes a novel regulator for chick eye morphogenesis.
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DOI：
10.1016/j.ydbio.2017.05.019
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发表时间：
2017-08-01
影响因子：
2.7
通讯作者：
Del Rio-Tsonis K
中科院分区：
文献类型：
--
作者：
Grajales-Esquivel E;Luz-Madrigal A;Bierly J;Haynes T;Reis ES;Han Z;Gutierrez C;McKinney Z;Tzekou A;Lambris JD;Tsonis PA;Del Rio-Tsonis K
补体成分与多种功能有关，包括神经发生、增殖、细胞迁移、分化、癌症以及最近的早期发育和再生。我们初步观察表明 C3a/C3aR 信号传导诱导雏鸡视网膜再生，随后我们分析了其在雏鸡眼睛形态发生中的作用。在眼睛发育过程中，视神经泡 (OV) 内陷形成双层视杯 (OC)，进而形成视网膜色素上皮 (RPE) 和神经视网膜。我们通过免疫荧光染色表明，C3 和 C3a 的受体（C3 的裂解和活性形式）C3aR 在 OV 和 OC 的眼睛形态发生过程中存在于鸡胚中。有趣的是，C3aR 在 OC 阶段主要定位于核区室。在 OV 阶段使用吗啉或针对 C3aR 的阻断抗体（抗 C3aR Ab）进行功能丧失研究，会导致眼睛缺陷，例如小眼球和眼睛腹侧部分的缺陷，从而导致缺损。当 C3aR 在 OC 阶段被破坏时，没有观察到此类缺陷。组织学分析表明，小眼球无法产生正常的视柄或闭合的 OC。背侧/腹侧图案缺陷伴随着腹侧标记 Pax2、cVax 和视黄酸合成酶 raldh-3 (aldh1a3) 结构域的扩展，Tbx5 和 raldh-1 (aldh1a1) 背侧表达的缺失以及腹侧 RPE 向神经上皮的重新特异化。此外，眼睛显示 Gli1 表达总体下降，核 β-catenin 分布发生变化，表明 Shh 和 Wnt 通路受到影响。最后，我们观察到显着的细胞死亡以及增殖细胞的减少，表明这两个过程都有助于小眼表型。我们的结果共同表明，C3aR 对于 OC 的正常形态发生是必需的。这是第一份涉及 C3aR 与眼睛发育的报告，揭示了迄今为止未被怀疑的鸡眼形态发生的调节因子。
Complement components have been implicated in a wide variety of functions including neurogenesis, proliferation, cell migration, differentiation, cancer, and more recently early development and regeneration. Following our initial observations indicating that C3a/C3aR signaling induces chick retina regeneration, we analyzed its role in chick eye morphogenesis. During eye development, the optic vesicle (OV) invaginates to generate a bilayer optic cup (OC) that gives rise to the retinal pigmented epithelium (RPE) and neural retina. We show by immunofluorescence staining that C3 and the receptor for C3a (the cleaved and active form of C3), C3aR, are present in chick embryos during eye morphogenesis in the OV and OC. Interestingly, C3aR is mainly localized in the nuclear compartment at the OC stage. Loss of function studies at the OV stage using morpholinos or a blocking antibody targeting the C3aR (anti-C3aR Ab), causes eye defects such as microphthalmia and defects in the ventral portion of the eye that result in coloboma. Such defects were not observed when C3aR was disrupted at the OC stage. Histological analysis demonstrated that microphthalmic eyes were unable to generate a normal optic stalk or a closed OC. The dorsal/ventral patterning defects were accompanied by an expansion of the ventral markers Pax2, cVax and retinoic acid synthesizing enzyme raldh-3 (aldh1a3) domains, an absence of the dorsal expression of Tbx5 and raldh-1 (aldh1a1) and a re-specification of the ventral RPE to neuroepithelium. In addition, the eyes showed overall decreased expression of Gli1 and a change in distribution of nuclear β-catenin, suggesting that Shh and Wnt pathways have been affected. Finally, we observed prominent cell death along with a decrease in proliferating cells, indicating that both processes contribute to the microphthalmic phenotype. Together our results show that C3aR is necessary for the proper morphogenesis of the OC. This is the first report implicating C3aR in eye development, revealing an unsuspected hitherto regulator for proper chick eye morphogenesis.
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影响因子：
2.7
作者：
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通讯作者：
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