SOX2 maintains quiescent progenitor cell state of retinal Muller glia

SOX2 维持视网膜米勒胶质细胞的静态祖细胞状态

• 批准号: 8449090
• 负责人: Ellen Ruth Weiss
• 金额: $ 34.03万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449090
• 关键词: Ablation; Address; Adult; Alleles; Architecture; Boxing; Cell Cycle; Cell division; Cells; Characteristics; Clinical; Competence; Coupled; Data; Development; ES01; Electroporation; Embryo; Embryonic Development; Eye; Genetic; Growth; Homeostasis; Human; Image; In Situ; Label; Laboratories; Left; Maintenance; Maps; Mediator of activation protein; Mitotic; Molecular; Morphology; Mus; Mutation; NOTCH1 gene; Neuraxis; Neuroglia; Neurons; Pattern; Population; Property; Radial; Regulation; Reporter; Reporting; Retina; Retinal; Retinal Degeneration; Role; Series; Signal Pathway; Signal Transduction; Spinal Cord; Stem cells; System; Techniques; Testing; Time; To specify; Venus; Work; base; cell behavior; cell transformation; embryonic stem cell; gain of function; in vivo; loss of function; mutant; nerve stem cell; optic cup; postnatal; premature; prevent; progenitor; regenerative; relating to nervous system; retinal progenitor cell; transcription factor

DESCRIPTION (provided by applicant): Located in discrete regions of the adult mammalian CNS, neural stems cells are specialized types of glia. M¿ller glia are the principal glial cell of he vertebrate retina and represent a dormant progenitor cell population in the adult CNS. These cells maintain retinal architecture, provide trophic support for neurons, and modulate neuronal activity, thus sustaining retinal homeostasis. M¿ller glia, however, do not irreversibly leave the progenitor state - they can re-enter the mitotic cycle to generate new neurons, and are therefore considered the key target cell for retinal regenerative studies. Unlike in other regions of the adut CNS, no documented cases of M¿ller glial cell transformation have been reported (Jadhav, 2009). These observations suggest the existence of tightly regulated molecular mechanisms that protect the retina from uncontrolled proliferation of M¿ller glial cells. We, and others, have previously shown that SOX2 is a core transcriptional regulator of pluripotentiality of embryonic stem cells (Avilion et al., 2003). In the developing and adult CNS, expression of SOX2 defines multipotent neural progenitor cells capable of giving rise to both neurons and glia. Several studies conducted in a variety of experimental systems demonstrated that, consistent with its expression pattern, SOX2 controls maintenance of neural progenitor cell identity; disruption of SOX2 function is associated with the loss of proliferative and differentiation capacity in neural progenitor cells, accompanied by the loss of their radial morphology (Favaro et al., 2009; Ferri et al., 2004; Pevny and Nicolis, 2010). Specifically, perturbation of SOX2 function by expression of dominant- interfering versions of SOX2 results in premature terminal differentiation of chick spinal cord progenitors (Bylund et al., 2003; Graham et al., 2003; Holmberg et al., 2008). Moreover, we have recently demonstrated that genetic ablation of SOX2 in the optic cup results in complete loss of retinal neuronal competence (Taranova et al 2006; Matsushima et al., 2011). However, it remains unknown what is the precise cellular mechanism regulated by SOX2 in the maintenance of adult progenitor identity. In this study, we will utilize mouse genetics combined with real-time imaging approaches to establish the role of SOX2 in the specification and function of M¿ller glial cells. Our preliminary data show that two key progenitor characteristics of M¿ller glia, their pseudoepithelial morphology and cell cycle quiescence, are disrupted following conditional genetic ablation of Sox2, leading to M¿ller cell depletion and retinal degeneration. Moreover, our studies have revealed that ablation of SOX2 in the postnatal retina results in aberrant cell division of M¿ller glial cells. Collectively, this work has led to the hypothesis tha SOX2 maintains M¿ller glial cell homeostasis by preventing their depletion through cell division. The determination of the role of the SOX2 signaling pathway in healthy and diseased retina is required to fully understand regulation of both the quiescent state and the regenerative potential of retinal M¿ller glia.

描述（由申请人提供）：神经干细胞位于成年哺乳动物中枢神经系统的离散区域，是一种特殊类型的神经胶质。米勒神经胶质细胞是脊椎动物视网膜的主要神经胶质细胞，在成年中枢神经系统中是一个休眠的祖细胞群。这些细胞维持视网膜结构，为神经元提供营养支持，并调节神经元活性，从而维持视网膜稳态。米然而，更小的神经胶质细胞不会不可逆地离开祖细胞状态-它们可以重新进入有丝分裂周期以产生新的神经元，因此被认为是视网膜再生研究的关键靶细胞。与成人CNS的其他区域不同，尚未报告M？ller神经胶质细胞转化的记录病例（Jadhav，2009）。这些观察结果表明，存在严格调控的分子机制，保护视网膜不受M？ller神经胶质细胞不受控制的增殖。我们和其他人 先前显示SOX 2是胚胎干细胞多能性的核心转录调节因子（Avalanet al.，2003年）。在发育和成年CNS中，SOX 2的表达定义了能够产生神经元和神经胶质的多能神经祖细胞。在多种实验系统中进行的几项研究表明，与其表达模式一致，SOX 2控制神经祖细胞身份的维持; SOX 2功能的破坏与神经祖细胞中增殖和分化能力的丧失相关，伴随着其放射状形态的丧失（Favaro et al.，2009; Ferri等人，2004年; Pevny和Nicolis，2010年）。具体地，通过表达显性干扰形式的SOX 2而干扰SOX 2功能导致鸡脊髓祖细胞的过早终末分化（Bylund等人，2003; Graham等人，2003; Holmberg等人，2008年）。此外，我们最近已经证明，视杯中SOX 2的遗传消融导致视网膜神经元能力的完全丧失（Taranova等人2006; Matsushima等人，2011年）。然而，目前尚不清楚SOX 2在维持成年祖细胞身份方面调节的精确细胞机制是什么。在这项研究中，我们将利用小鼠遗传学结合实时成像方法来建立SOX 2在M？ller神经胶质细胞的特化和功能中的作用。我们的初步数据表明，两个关键的祖细胞特性的M？ller胶质细胞，其假上皮形态和细胞周期静止，被破坏后，条件性基因消融的Sox 2，导致M？ller细胞耗竭和视网膜变性。此外，我们的研究表明，出生后视网膜中SOX 2的消融导致M？ller神经胶质细胞的细胞分裂异常。总的来说，这项工作导致了这样一种假设，即SOX 2通过防止细胞分裂而耗尽来维持M？ller胶质细胞的稳态。确定SOX 2信号通路在健康和患病视网膜中的作用是完全理解视网膜M？ller胶质细胞的静止状态和再生潜力的调节所必需的。