Cone Photoreceptors Develop Normally in the Absence of Functional Rod Photoreceptors in a Transgenic Swine Model of Retinitis Pigmentosa
Cone Photoreceptors Develop Normally in the Absence of Functional Rod Photoreceptors in a Transgenic Swine Model of Retinitis Pigmentosa
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DOI：
10.1167/iovs.13-13724
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发表时间：
2014-04-01
影响因子：
4.4
通讯作者：
McCall, Maureen A.
中科院分区：
文献类型：
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作者：
de Castro, Juan P. Fernandez;Scott, Patrick A.;McCall, Maureen A.
目的.人类和猪的视网膜在形态和功能上有相似之处。在缺乏灵长类动物模型的情况下，猪是研究视网膜功能和疾病的有吸引力的模型，其锥状体丰富的视觉条纹，我们操纵其基因组的能力，以及视杆和视锥光感受器对疾病的易感性差异。我们的特点是正常的发展锥功能和随后下降的P23 H视紫红质转基因（TgP 23 H）小型猪模型的常染色体显性RP。TgP 23 H小型猪53-1的精液与家猪授精，产生TgP 23 H和Wt杂种同窝仔。在出生后第14天（P）至第120天之间使用ERG评估视网膜功能。记录视网膜神经节细胞（RGC）对几种强度的全场刺激的反应。使用光学和电子显微镜评估视网膜形态。暗视视网膜功能在Wt猪中成熟至P60，但在TgP 23 H猪中从未发育。Wt和TgP 23 H明视觉在P30时相似地成熟，并且在P60时发散，其中TgP 23 H锥视觉下降。在所有年龄段，具有视觉诱发反应的TgP 23 H RGC较少，并且它们对光的反应受到损害。光感受器的形态学变化反映了这些功能变化。TgP 23 H猪缺乏早期暗视功能表明它是RP侵袭性形式的模型。在这个哺乳动物模型的RP，正常的锥功能的发展独立于杆功能。因此，它的视网膜代表了一个系统，其中可以开发救援视锥细胞的疗法来延长RP患者的明视功能。
PURPOSE. Human and swine retinas have morphological and functional similarities. In the absence of primate models, the swine is an attractive model to study retinal function and disease, with its cone-rich visual streak, our ability to manipulate their genome, and the differences in susceptibility of rod and cone photoreceptors to disease. We characterized the normal development of cone function and its subsequent decline in a P23H rhodopsin transgenic (TgP23H) miniswine model of autosomal dominant RP.METHODS. Semen from TgP23H miniswine 53-1 inseminated domestic swine and produced TgP23H and Wt hybrid littermates. Retinal function was evaluated using ERGs between postnatal days (P) 14 and 120. Retinal ganglion cell (RGC) responses were recorded to full-field stimuli at several intensities. Retinal morphology was assessed using light and electron microscopy.RESULTS. Scotopic retinal function matures in Wt pigs up to P60, but never develops in TgP23H pigs. Wt and TgP23H photopic vision matures similarly up to P30 and diverges at P60 where TgP23H cone vision declines. There are fewer TgP23H RGCs with visually evoked responses at all ages and their response to light is compromised. Photoreceptor morphological changes mirror these functional changes.CONCLUSIONS. Lack of early scotopic function in TgP23H swine suggests it as a model of an aggressive form of RP. In this mammalian model of RP, normal cone function develops independent of rod function. Therefore, its retina represents a system in which therapies to rescue cones can be developed to prolong photopic visual function in RP patients.