Mutant Ahi1 Affects Retinal Axon Projection in Zebrafish via Toxic Gain of Function
Mutant Ahi1 Affects Retinal Axon Projection in Zebrafish via Toxic Gain of Function
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突变体 Ahi1 通过毒性功能获得影响斑马鱼视网膜轴突投射
DOI：
10.3389/fncel.2019.00081
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发表时间：
2019-03
影响因子：
5.3
通讯作者：
Li Xiao-Jiang
中科院分区：
文献类型：
--
作者：
Zhu Louyin;Chen Laidiang;Yan Lingya;Perkins Brian D.;Li Shihua;Li Baoming;Xu Hong A.;Li Xiao-Jiang
Joubert综合征（JBTS）是一种与小脑和脑干畸形相关的遗传性常染色体隐性遗传病，可由Abelson辅助整合位点-1（AHI 1）基因突变引起。虽然人类的AHI 1突变导致JBTS的小脑发育异常和轴突交叉受损，但这些表型在各种Ahi 1突变的小鼠模型中并不稳健或不存在。AHI 1含有N-末端卷曲螺旋结构域、多个WD 40重复序列和C-末端Src同源3（SH 3）结构域，表明AHI 1作为信号或支架蛋白发挥功能。由于人类中的大多数AHI 1突变可导致缺失WD 40重复序列和SH 3结构域的截短AHI 1蛋白，因此仍不清楚突变AHI 1是否通过截短AHI 1的功能获得机制来减轻毒性。由于斑马鱼和人类中的Ahi 1具有相似的N末端区域，并且具有小鼠Ahi 1中不存在的卷曲螺旋结构域，因此我们使用斑马鱼作为模型来研究Ahi 1突变是否会影响轴突交叉。利用原位杂交技术，我们发现ahi 1在斑马鱼眼组织中高度表达，特别是在视网膜中，使我们能够检查其对视网膜神经节细胞（RGC）投影和眼睛形态的影响。我们将morpholino注射到斑马鱼胚胎中，可以产生缺失完整WD 40重复序列的突变Ahi 1，并在注射后4 dpf（受精后天数）的幼虫中发现RGC轴突错误投射和眼发育不良。然而，ahi 1 null斑马鱼显示正常的RGC轴突投射和眼形态。然后，我们使用CRISPR/Cas9来产生截短的ahi 1，并在RGC轴突投射中发现了与注射ahi 1吗啉代的那些类似的缺陷。因此，在斑马鱼异常的视网膜轴突投射是由突变ahi 1的存在，而不是ahi 1的损失，这表明突变ahi 1可能会影响轴突交叉通过毒性获得的功能。
Joubert syndrome (JBTS) is an inherited autosomal recessive disorder associated with cerebellum and brainstem malformation and can be caused by mutations in the Abelson helper integration site-1 (AHI1) gene. Although AHI1 mutations in humans cause abnormal cerebellar development and impaired axonal decussation in JBTS, these phenotypes are not robust or are absent in various mouse models with Ahi1 mutations. AHI1 contains an N-terminal coiled-coil domain, multiple WD40 repeats, and a C-terminal Src homology 3 (SH3) domain, suggesting that AHI1 functions as a signaling or scaffolding protein. Since most AHI1 mutations in humans can result in truncated AHI1 proteins lacking WD40 repeats and the SH3 domain, it remains unclear whether mutant AHI1 elicits toxicity via a gain-of-function mechanism by the truncated AHI1. Because Ahi1 in zebrafish and humans share a similar N-terminal region with a coiled-coil domain that is absent in mouse Ahi1, we used zebrafish as a model to investigate whether Ahi1 mutations could affect axonal decussation. Using in situ hybridization, we found that ahi1 is highly expressed in zebrafish ocular tissues, especially in retina, allowing us to examine its effect on retinal ganglion cell (RGC) projection and eye morphology. We injected a morpholino to zebrafish embryos, which can generate mutant Ahi1 lacking the intact WD40 repeats, and found RGC axon misprojection and ocular dysplasia in 4 dpf (days post-fertilization) larvae after the injection. However, ahi1 null zebrafish showed normal RGC axon projection and ocular morphology. We then used CRISPR/Cas9 to generate truncated ahi1 and also found similar defects in the RGC axon projection as seen in those injected with ahi1 morpholino. Thus, the aberrant retinal axon projection in zebrafish is caused by the presence of mutant ahi1 rather than the loss of ahi1, suggesting that mutant Ahi1 may affect axonal decussation via toxic gain of function.
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影响因子：
2.5
作者：
Doering, Jennifer E.;Kane, Kelly;Hsiao, Yi-Chun;Yao, Cong;Shi, Bingxing;Slowik, Amber D.;Dhagat, Bakul;Scott, Delisha D.;Ault, Jeffrey G.;Page-McCaw, Patrick S.;Ferland, Russell J.
通讯作者：
Ferland, Russell J.
Ahi1 缺失会损害 BM88/Cend1 介导的神经元分化，从而影响早期发育
DOI：
10.1523/jneurosci.0119-13.2013
发表时间：
2013-05-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Weng L;Lin YF;Li AL;Wang CE;Yan S;Sun M;Gaertig MA;Mitha N;Kosaka J;Wakabayashi T;Xu X;Tang B;Li S;Li XJ
通讯作者：
Li XJ
影响因子：
15.9
作者：
Sheng, Guoqing;Xu, Xingshun;Li, Xiao-Jiang
通讯作者：
Li, Xiao-Jiang
影响因子：
16.2
作者：
Hutson, LD;Chien, CB
通讯作者：
Chien, CB
影响因子：
5.2
作者：
Ingason, Andres;Sigmundsson, Thordur;Stefansson, Hreinn
通讯作者：
Stefansson, Hreinn