A high content, small molecule screen identifies candidate molecular pathways that regulate rod photoreceptor outer segment renewal.
A high content, small molecule screen identifies candidate molecular pathways that regulate rod photoreceptor outer segment renewal.
复制标题
DOI：
10.1038/s41598-018-32336-y
复制
发表时间：
2018-09-18
影响因子：
4.6
通讯作者：
Jensen AM
中科院分区：
文献类型：
--
作者：
Campbell LJ;West MC;Jensen AM
脊椎动物杆状感光器的外段是一个高度修饰的纤毛，由许多离散的膜盘组成，这些膜盘充满了光转导所需的蛋白质机制。独特的外节结构每天更新，在外节的底部生长，在那里形成新的视盘，在远端脱落，在那里旧的视盘被视网膜色素上皮吞噬。为了了解外节段更新是如何调节以维持外节段长度和功能的，我们使用了转基因斑马鱼(HSP70：HA-mCherryTM)的小分子筛选方法，斑马鱼表达外节段更新的遗传编码标记。我们确定了具有已知生物活性的化合物，这些化合物影响五个内容区域：外节生长、外节脱落、脱落外节尖端的清除、视紫红质错误定位和纤毛边缘区的分化。已鉴定的化合物靶向的信号通路包括外段生长中的环氧合酶、外段脱落中的γ分泌酶和RPE吞噬过程中的mTOR。该屏幕产生的数据为进一步研究调节光感受器外节段更新的信号通路提供了基础。
The outer segment of the vertebrate rod photoreceptor is a highly modified cilium composed of many discrete membranous discs that are filled with the protein machinery necessary for phototransduction. The unique outer segment structure is renewed daily with growth at the base of the outer segment where new discs are formed and shedding at the distal end where old discs are phagocytized by the retinal pigment epithelium. In order to understand how outer segment renewal is regulated to maintain outer segment length and function, we used a small molecule screening approach with the transgenic (hsp70:HA-mCherryTM) zebrafish, which expresses a genetically-encoded marker of outer segment renewal. We identified compounds with known bioactivity that affect five content areas: outer segment growth, outer segment shedding, clearance of shed outer segment tips, Rhodopsin mislocalization, and differentiation at the ciliary marginal zone. Signaling pathways that are targeted by the identified compounds include cyclooxygenase in outer segment growth, γ-Secretase in outer segment shedding, and mTor in RPE phagocytosis. The data generated by this screen provides a foundation for further investigation of the signaling pathways that regulate photoreceptor outer segment renewal.
登录
查看更多内容
影响因子：
8
作者：
Brockerhoff, Susan E.;Fadool, James M.
通讯作者：
Fadool, James M.
影响因子：
4.4
作者：
Fan, Jie;Rohrer, Baerbel;Crouch, Rosalie K.
通讯作者：
Crouch, Rosalie K.
影响因子：
4.8
作者：
Damek-Poprawa, Monika;Diemer, Tanja;Boesze-Battaglia, Kathleen
通讯作者：
Boesze-Battaglia, Kathleen
影响因子：
4.3
作者：
Dooley, Christopher M.;Schwarz, Heinz;Geisler, Robert
通讯作者：
Geisler, Robert
影响因子：
3.5
作者：
D'Cruz, PM;Yasumura, D;Vollrath, D
通讯作者：
Vollrath, D