Overlapping and distinct pRb pathways in the mammalian auditory and vestibular organs
Overlapping and distinct pRb pathways in the mammalian auditory and vestibular organs
复制标题
DOI：
10.4161/cc.10.2.14640
复制
发表时间：
2011-01-15
期刊：
影响因子：
4.3
通讯作者：
Chen, Zheng-Yi
中科院分区：
文献类型：
--
作者：
Huang, Mingqian;Sage, Cyrille;Chen, Zheng-Yi
视网膜母细胞瘤基因（Rb 1）是发育中的小鼠内耳中适当的细胞周期退出所必需的，并且其在胚胎中的缺失导致分化成毛细胞和支持细胞的感觉祖细胞的增殖。在条件性毛细胞Rb 1基因敲除小鼠中，Pou 4f 3-Cre-pRb（-/-）、pRb（-/-）椭圆囊毛细胞分化并存活至成年期，而pRb（-/-）耳蜗毛细胞的分化和存活受损。为了全面调查哺乳动物内耳中的pRb通路，我们对pRb（-/-）耳蜗和椭圆囊进行了微阵列分析。比较分析表明，pRb（-/-）耳蜗和椭圆囊共同的核心通路以E2 F为中心，是介导pRb功能的关键通路。大多数差异表达的基因和富集的途径不是共享的，而是与pRb（-/-）耳蜗或椭圆囊唯一相关的。在pRb（-/-）耳蜗中，参与早期内耳发育的通路如Wnt/β-catenin和Notch富集，而参与增殖和存活的通路在pRb（-/-）椭圆囊中富集。聚类分析表明，pRb（-/-）内耳具有年轻对照内耳的特征，表明分化延迟。我们建立了一个转基因小鼠模型（ER-Cre-pRb（flox/flox）），其中Rb 1可以在出生后急性缺失。急性Rb 1缺失在成年小鼠未能诱导增殖或细胞死亡的内耳，强烈表明，Rb 1损失在这些有丝分裂后组织可以有效地补偿，或有丝分裂后室的pRb介导的变化导致的事件是功能上不可逆的，一旦制定。因此，这项研究支持的概念，PRB调节的途径相关的毛细胞发育，包括增殖，分化和生存，主要在早期发展。
Retinoblastoma gene (Rb1) is required for proper cell cycle exit in the developing mouse inner ear and its deletion in the embryo leads to proliferation of sensory progenitor cells that differentiate into hair cells and supporting cells. In a conditional hair cell Rb1 knockout mouse, Pou4f3-Cre-pRb(-/-), pRb(-/-) utricular hair cells differentiate and survive into adulthood whereas differentiation and survival of pRb(-/-) cochlear hair cells are impaired. To comprehensively survey the pRb pathway in the mammalian inner ear, we performed microarray analysis of pRb(-/-) cochlea and utricle. The comparative analysis shows that the core pathway shared between pRb(-/-) cochlea and utricle is centered on E2F, the key pathway that mediates pRb function. A majority of differentially expressed genes and enriched pathways are not shared but uniquely associated with pRb(-/-) cochlea or utricle. In pRb(-/-) cochlea, pathways involved in early inner ear development such as Wnt/beta-catenin and Notch were enriched, whereas pathways involved in proliferation and survival are enriched in pRb(-/-) utricle. Clustering analysis showed that the pRb(-/-) inner ear has characteristics of a younger control inner ear, an indication of delayed differentiation. We created a transgenic mouse model (ER-Cre-pRb(flox/flox)) in which Rb1 can be acutely deleted postnatally. Acute Rb1 deletion in the adult mouse fails to induce proliferation or cell death in inner ear, strongly indicating that Rb1 loss in these postmitotic tissues can be effectively compensated for, or that pRb-mediated changes in the postmitotic compartment result in events that are functionally irreversible once enacted. This study thus supports the concept that pRb-regulated pathways relevant to hair cell development, encompassing proliferation, differentiation and survival, act predominantly during early development.