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（由申请方提供）：在发育过程中，在分隔两个大脑皮质的背侧端脑中线（DTM）中形成独特的组织。在这些组织中有皮质hem，我们最近发现它是海马的组织者，还有脉络丛，它是脑脊液（CSF）的来源。脉络丛是一个众所周知的组织，具有重要的治疗潜力，但其发展是相当了解甚少。此外，DTM发育失败是前脑无裂畸形（HPE）的中心特征，HPE是人类前脑最常见的先天性畸形。本提案的目标是阐明控制DTM发展的机制和遗传网络，这将为HPE发病机制和培养中脉络丛的产生提供信息，以供临床应用。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，在小鼠中产生Bmp的顶板的基因消融导致DTM诱导缺陷，这可以单独用外源性Bmp4来挽救。尽管如此，关于BMP信号传导和形态发生活性的基本问题仍然没有答案。遗传性顶板消融还会导致背部HPE，这导致了有关人类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表型是如何出现的。然而，在这个网络中，对Bmp相互作用的了解非常差，包括抑制Bmp途径以限制DTM命运并定位其边界的因素的身份。我们先前使用顶板消融模型来暗示Bmps在体内DTM诱导中。最近，我们证明了培养的皮质神经前体细胞（NPC）的反应与Bmp4作为DTM形态发生一致，并确定了LIM同源结构域转录因子Lhx2作为皮质选择基因，抑制皮质hem命运。在初步研究中，我们暗示成纤维细胞生长因子8（Fgf8）作为第二个DTM命运抑制剂，并描述了使能工具，包括一个新的BMP活性报告小鼠，微流体培养系统，DTM发展的数学模型。这些发现和工具为我们提供了一个独特的机会，在脊椎动物中枢神经系统模型系统，以解决形态生物学，发育边界的形成，以及BMP活性调节除了HPE发病机制和脉络丛命运规范的基本问题。在这个建议中，我们使用验证在体内，在体外，微流体，并在计算机工具来定义的分子机制和遗传网络，直接DTM的发展，重点对BMP的活动和调节it.Public健康相关的因素：这个项目的目标是更好地了解网络，管理端脑背中线区域的发展。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见解，也与越来越多的与神经干细胞缺陷相关的精神和神经疾病，以及旨在治疗这些脑部疾病的NSC和其他干细胞策略有关。