OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness
OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness
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DOI：
10.1172/jci72722
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
Swaroop, Anand
中科院分区：
文献类型：
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作者：
Roger, Jerome E.;Hiriyanna, Avinash;Swaroop, Anand
Leber先天性黑蒙（LCA）是一组早发性致盲性疾病，其特征为视力丧失、不自主眼球运动和不可记录的视网膜电图（ERG）。至少有19个基因与LCA相关，通常是隐性的;然而，同源结构域转录因子CRX的突变导致LCA的常染色体显性形式。CRX相关LCA的机制尚不清楚。在这里，我们确定了一个自发的小鼠突变与Crx（RiP）的移码突变。我们确定CrxRiP是一种显性突变，导致先天性失明，ERG无法记录反应，感光细胞分化停滞，无相关变性。LCA相关显性CRX移码突变在小鼠视网膜中的表达模拟了CrxRiP表型，其通过WT CRX的过表达而被拯救。使用深度RNA测序的全转录组分析揭示了CrxRiP视网膜中视杆细胞分化因子NRL的进行性和完全丧失。NRL的表达部分恢复了Crx（RiP/+）小鼠的视杆发育。我们表明，同源框转录因子OTX 2在Nrl启动子处的结合在CrxRiP小鼠中被消除，并且OTX 2的异位表达挽救了视杆细胞分化缺陷。总之，我们的数据表明0 TX 2在发育中的视杆中维持Nrl表达以巩固视杆命运。我们的研究提供了CRX突变相关的先天性失明的见解，并应有助于治疗设计。
Leber congenital amaurosis (LCA) encompasses a set of early-onset blinding diseases that are characterized by vision loss, involuntary eye movement, and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA, which is typically recessive; however, mutations in homeodomain transcription factor CRX lead to an autosomal dominant form of LCA. The mechanism of CRX-associated LCA is not understood. Here, we identified a spontaneous mouse mutant with a frameshift mutation in Crx (Crx(RiP)). We determined that CrxRiP is a dominant mutation that results in congenital blindness with nonrecordable response by ERG and arrested photoreceptor differentiation with no associated degeneration. Expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the CrxRiP phenotype, which was rescued by overexpression of WT CRX. Whole-transcriptome profiling using deep RNA sequencing revealed progressive and complete loss of rod differentiation factor NRL in CrxRiP retinas. Expression of NRL partially restored rod development in Crx(RiP/+) mice. We show that the binding of homeobox transcription factor OTX2 at the Nrl promoter was obliterated in CrxRiP mice and ectopic expression of OTX2 rescued the rod differentiation defect. Together, our data indicate that OTX2 maintains Nrl expression in developing rods to consolidate rod fate. Our studies provide insights into CRX mutation-associated congenital blindness and should assist in therapeutic design.