Abnormalities of the vitreoretinal interface caused by dysregulated Hedgehog signaling during retinal development
Abnormalities of the vitreoretinal interface caused by dysregulated Hedgehog signaling during retinal development
复制标题
DOI：
10.1093/hmg/ddg356
复制
发表时间：
2003-12-15
影响因子：
3.5
通讯作者：
Wallace, VA
中科院分区：
文献类型：
--
作者：
Black, GCM;Mazerolle, CJ;Wallace, VA
编码 Hedgehog (Hh) 受体的 Patched (PTCH) 突变是基底细胞痣综合征 (BCNS) 的基础，除了肿瘤易感性之外，还与多种“模式”缺陷相关。然而，BCNS 中 Hh 依赖性组织的潜在模式问题的基础及其对组织稳态的长期影响尚不清楚。 Hh 信号传导是哺乳动物视网膜正常生长和组织所必需的，我们发现 PtchlacZ(+/-) 小鼠表现出与 BCNS 患者相似的玻璃体视网膜异常。 PtchlacZ(+/-) 小鼠的视网膜表现出异常的细胞周期调节，最终导致光感受器发育不良和 Muller 细胞衍生的神经胶质增生。在 BCNS 中，视网膜内神经胶质反应导致视网膜前膜 (ERM) 形成，这是视网膜表面的增殖和收缩反应。 ERM 是导致普通人群（尤其是老年人）视力严重丧失的一个原因。我们假设 Muller 细胞 Hh 信号传导的改变可能在此类与年龄相关的“特发性”ERM 的发病机制中发挥作用。
Mutations in Patched (PTCH), encoding the Hedgehog (Hh) receptor, underlie Basal Cell Naevus syndrome (BCNS) and, in addition to tumor predisposition, are associated with a wide range of 'patterning' defects. The basis for the underlying patterning problems in Hh-dependent tissues in BCNS and their long-term consequences on tissue homeostasis are, however, not known. Hh signaling is required for normal growth and organization of the mammalian retina and we show that PtchlacZ(+/-) mice exhibit vitreoretinal abnormalities resembling those found in BCNS patients. The retinas of PtchlacZ(+/-) mice exhibit abnormal cell cycle regulation, which culminates in photoreceptor dysplasia and Muller cell-derived gliosis. In BCNS, the intraretinal glial response results in epiretinal membrane (ERM) formation, a proliferative and contractile response on the retinal surface. ERMs are a cause of significant visual loss in the general, especially elderly, population. We hypothesize that alteration of Muller cell Hh signaling may play a role in the pathogenesis of such age-related 'idiopathic' ERMs.