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）：在发育期间，在背脑脑中线（DTM）中形成独特的组织，将两个脑皮质分开。这些组织中有皮质下摆，我们最近确定为海马组织者，而脉络膜是脑脊液（CSF）的脉络丛。脉络丛是一种众所周知的组织，具有明显的治疗潜力，但其发育知之甚少。此外，DTM开发失败是Holoprosencephaly（HPE）的核心特征，这是人类前脑最常见的先天性畸形。该提案的目的是阐明控制DTM发育的机制和遗传网络，这将为HPE发病机理和临床应用中脉络膜丛的产生提供信息。先前的研究已经确定了DTM发育中骨形态发生蛋白（BMP）的核心作用。例如，在小鼠中产生BMP的屋顶板的遗传消融会导致DTM诱导缺陷，仅凭外源性BMP4可以营救。尽管如此，有关BMP信号传导和形态学活性的基本问题仍未得到解答。遗传屋顶板消融还引起了HPE的背面形式，这导致了有关人类HPE患者的新发现以及前脑发育的信号传导网络模型，该模型可以解释人类HPE表型的不同。但是，在该网络中，对BMP相互作用的见解显然很差，包括抑制BMP途径限制DTM命运并定位边界的因素的身份。我们先前使用屋顶板消融模型将BMP牵涉到体内DTM诱导中。最近，我们证明了与BMP4一致的培养的皮质神经前体细胞（NPC）的反应，与BMP4相一致，并确定了抑制皮质下摆命运的皮质选择域转录因子LHX2作为皮质选择器基因。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命运抑制器，并描述了包括新的BMP活性报告小鼠，微流体培养系统和DTM开发的数学模型的启用工具。这些发现和工具为我们提供了独特的机会，在CNS模型系统中，除了HPE发病机理和脉络膜plexus命运规范外，还解决了形态生物学，发育边界形成和BMP活动调节的基本问题。在此提案中，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直接DTM开发的分子机制和遗传网络，重点是BMP活性及其调节因素。公共卫生相关性：该项目的目标是更好地理解脑脑中间线区域发展的网络。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的先天缺陷的见解，以及与神经干细胞缺陷相关的精神病和神经系统疾病的越来越多，以及旨在治疗这些脑疾病的NSC和其他干细胞策略。