The Morphogen and Selector Gene Network in the Dorsal Telencephalic Midline

背侧端脑中线的形态发生素和选择基因网络

• 批准号: 7584404
• 负责人: EDWIN S MONUKI
• 金额: $ 31.62万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584404
• 关键词: Ablation; Address; Biological Models; Bone Morphogenetic Proteins; Brain Diseases; Cells; Cerebral cortex; Cerebrospinal Fluid; Complement; Computer Simulation; Congenital Abnormality; Cultured Cells; Data; Defect; Development; Developmental Biology; Disease; Dorsal; Feedback; Fibroblast Growth Factor 8; Forebrain Development; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Goals; Hippocampus (Brain); Holoprosencephaly; Human; In Vitro; Level of Evidence; Microfluidics; Modeling; Molecular; Multiprotein Complexes; Mus; Neurologic; Nuclear; Numbers; Pathogenesis; Pathway interactions; Patients; Phenotype; Positioning Attribute; Property; Prosencephalon; Public Health; Regulation; Reporter; Role; Signal Transduction; Source; Specific qualifier value; Stem cells; Structure of choroid plexus; Supine Position; System; Telencephalon; Testing; Therapeutic; Tissues; base; clinical application; concept; homeodomain; in vivo; insight; mathematical model; morphogens; nerve stem cell; network models; precursor cell; relating to nervous system; response; tool; transcription factor

DESCRIPTION (provided by applicant): During development, distinctive tissues form in the dorsal telencephalic midline (DTM) that separates the two cerebral cortices. Among these tissues are the cortical hem, which we recently identified as being a hippocampal organizer, and the choroid plexus, the source of cerebrospinal fluid (CSF). The choroid plexus is a well-known tissue with significant therapeutic potential, but its development is quite poorly understood. Moreover, failed DTM development is a central feature of holoprosencephaly (HPE), the most common congenital malformation of the human forebrain. The goal of this proposal is to elucidate the mechanisms and genetic network that govern DTM development, which will inform HPE pathogenesis and the generation of choroid plexus in culture for clinical applications. Previous studies have established central roles for the bone morphogenetic proteins (Bmps) in DTM development. For example, genetic ablation of the Bmp-producing roof plate in mice causes DTM induction deficits that can be rescued with exogenous Bmp4 alone. Nonetheless, fundamental questions about Bmp signaling and morphogenic activity remain unanswered. Genetic roof plate ablation also causes a dorsal form of HPE, which led to new discoveries about human HPE patients and a signaling network model of forebrain development that can explain how distinct human HPE phenotypes arise. However, within this network, insights into Bmp interactions are notably poor, including the identity of factors that inhibit the Bmp pathway to restrict DTM fates and position their borders. We previously used the roof plate ablation model to implicate Bmps in DTM induction in vivo. More recently, we demonstrated responses in cultured cortical neural precursor cells (NPCs) consistent with Bmp4 acting as a DTM morphogen, and identified the LIM homeodomain transcription factor Lhx2 as a cortical selector gene that suppresses cortical hem fate. In Preliminary Studies, we implicate fibroblast growth factor 8 (Fgf8) as a second DTM fate suppressor and describe enabling tools that include a new Bmp activity reporter mouse, a microfluidic culture system, and a mathematical model of DTM development. These findings and tools provide us with a unique opportunity, among vertebrate CNS model systems, to address fundamental questions in morphogen biology, developmental border formation, and Bmp activity regulation in addition to HPE pathogenesis and choroid plexus fate specification. In this proposal, we use validated in vivo, in vitro, microfluidic, and in silico tools to define the molecular mechanisms and genetic network that direct DTM development, focusing on Bmp activity and the factors that modulate it. PUBLIC HEALTH RELEVANCE: The goal for this project is to better understand the network that governs development of the dorsal midline region in the telencephalon. The proposal is based on a signaling network model we developed that can explain holoprosencephaly, the most common congenital malformation of the human forebrain. The relevance of this project to public health derive mainly from the insights into this common birth defects, but also to the increasing number of psychiatric and neurologic diseases associated with neural stem cell defects, and to NSC and other stem cell strategies aimed at treating these brain disorders.

描述（由申请人提供）：在发育过程中，在分隔两个大脑皮层的背侧端脑中线（DTM）中形成独特的组织。这些组织包括皮质下缘（我们最近确定其为海马组织者）和脉络丛（脑脊液 (CSF) 的来源）。脉络丛是一种众所周知的具有显着治疗潜力的组织，但对其发育却知之甚少。此外，DTM 发育失败是前脑无裂畸形 (HPE) 的一个主要特征，HPE 是人类前脑最常见的先天性畸形。该提案的目标是阐明控制 DTM 发展的机制和遗传网络，这将为临床应用的 HPE 发病机制和培养物中脉络丛的生成提供信息。先前的研究已经确定了骨形态发生蛋白 (Bmps) 在 DTM 发育中的核心作用。例如，小鼠中产生 Bmp 的顶板的基因消融会导致 DTM 诱导缺陷，而这种缺陷可以单独用外源 Bmp4 来挽救。尽管如此，有关 Bmp 信号传导和形态发生活性的基本问题仍未得到解答。遗传性顶板消融也会导致 HPE 的背侧形式，这导致了关于人类 HPE 患者的新发现以及前脑发育的信号网络模型，该模型可以解释不同的人类 HPE 表型是如何产生的。然而，在这个网络中，对 Bmp 相互作用的了解明显很差，包括抑制 Bmp 通路以限制 DTM 命运并定位其边界的因素的识别。我们之前使用顶板消融模型将 Bmps 与 DTM 体内诱导相关。最近，我们在培养的皮质神经前体细胞 (NPC) 中证明了与 Bmp4 作为 DTM 形态发生素一致的反应，并确定了 LIM 同源域转录因子 Lhx2 作为抑制皮质 hem 命运的皮质选择基因。在初步研究中，我们将成纤维细胞生长因子 8 (Fgf8) 视为第二个 DTM 命运抑制因子，并描述了支持工具，包括新的 Bmp 活性报告小鼠、微流体培养系统和 DTM 开发的数学模型。这些发现和工具为我们在脊椎动物 CNS 模型系统中提供了一个独特的机会，除了 HPE 发病机制和脉络丛命运规范之外，还可以解决形态发生素生物学、发育边界形成和 Bmp 活性调节等基本问题。在本提案中，我们使用经过验证的体内、体外、微流体和计算机工具来定义指导 DTM 开发的分子机制和遗传网络，重点关注 Bmp 活性及其调节因素。公共健康相关性：该项目的目标是更好地了解控制端脑背侧中线区域发育的网络。该提案基于我们开发的信号网络模型，该模型可以解释前脑无裂畸形，这是人类前脑最常见的先天性畸形。该项目与公共卫生的相关性主要源于对这种常见出生缺陷的深入了解，而且还涉及与神经干细胞缺陷相关的越来越多的精神和神经系统疾病，以及旨在治疗这些大脑的 NSC 和其他干细胞策略失调。