Zfhx3 modulates retinal sensitivity and circadian responses to light.
Zfhx3 modulates retinal sensitivity and circadian responses to light.
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Zfhx3调节视网膜对光的敏感性和昼夜节律反应。
DOI：
10.1096/fj.202100563r
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发表时间：
2021-09
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转录因子的突变通常表现出与其复杂的表达模式和多个调控靶点相关的多效性效应。锌指同源框3（ZFHX 3）转录因子中的一种这样的突变，短路（Sci，Zfhx 3Sci/+），与小鼠中的显著昼夜节律缺陷相关。然而，鉴于其视网膜表达的证据，我们开始使用分子，细胞，行为和电生理措施来建立突变对视网膜功能的影响。免疫组织化学证实了ZFHX 3在多种视网膜细胞类型中的表达，包括GABA能无长突细胞和视网膜神经节细胞，包括固有光敏视网膜神经节细胞（ipRGC）。Zfhx 3Sci/+突变体在自发活动和昼夜节律夹带中显示降低的光响应性，相对正常的视网膜电图和视动反应，但表现出意想不到的瞳孔反射表型，灵敏度显著增加。此外，Zfhx 3Sci/+视网膜的多个电极阵列记录显示ipRGC光响应的灵敏度增加。
Mutations in transcription factors often exhibit pleiotropic effects related to their complex expression patterns and multiple regulatory targets. One such mutation in the zinc finger homeobox 3 (ZFHX3) transcription factor, short circuit (Sci, Zfhx3Sci/+ ), is associated with significant circadian deficits in mice. However, given evidence of its retinal expression, we set out to establish the effects of the mutation on retinal function using molecular, cellular, behavioral and electrophysiological measures. Immunohistochemistry confirms the expression of ZFHX3 in multiple retinal cell types, including GABAergic amacrine cells and retinal ganglion cells including intrinsically photosensitive retinal ganglion cells (ipRGCs). Zfhx3Sci/+ mutants display reduced light responsiveness in locomotor activity and circadian entrainment, relatively normal electroretinogram and optomotor responses but exhibit an unexpected pupillary reflex phenotype with markedly increased sensitivity. Furthermore, multiple electrode array recordings of Zfhx3Sci/+ retina show an increased sensitivity of ipRGC light responses.