Doctoral Dissertation Improvement: Novel Transgenic Mouse Model for Human Fetal Encephalization and Cranial Development

博士论文改进：用于人类胎儿脑化和颅骨发育的新型转基因小鼠模型

• 批准号: 0725338
• 负责人: Matthew Ravosa
• 金额: $ 1.5万
• 依托单位: Northwestern University at Chicago
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0725338&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Improvement; Novel; Transgenic

Some of the major events during primate evolution, as well as primate development, are marked by profound increases in relative brain size. Indeed, the origins of many primate groups, including modern humans, have been characterized by surprising changes in the brain and skull. Although brain expansion has long been thought to influence skull shape, there is a great disparity between the interspecific and intraspecific findings regarding which factors differentially influence the organization of the primate skull. This detracts from our understanding of the major determinants of skull form in living and extinct primates. To rectify this shortcoming, the proposed analyses use novel samples and techniques to test the hypothesis that variation in the shape of the cranial base and vault is significantly correlated with variation in brain size. To address the scarcity of experimental models of human brain evolution and fetal growth, genetically modified mice expressing a stabilized form of the beta-catenin protein will be used to isolate the effects of relative brain size on the development and morphology of the cranial base and vault. These mice develop highly enlarged brains due to an increase in neural precursor cells and, as the beta-catenin transgene is expressed only in such brain cells, differences in skull shape between wild-type and transgenic littermates are predicted to result solely from differences in brain size and shape. By focusing on the prenatal period, which is characterized by remarkable brain growth, this project will benefit our understanding of a critically important period when major structural and functional inter-relationships are established within the skull. In particular, such data will be important for understanding the evolution of primate skull form as well as for basic translational research on normal and pathological skull development in humans.To examine the prenatal organization of the skull, transgenic mice will be analyzed at several stages of development using magnetic resonance imaging (MRI), microcomputed tomography (microCT), 3D geometric morphometrics, histology, and immunohistochemistry. Three-dimensional macroanatomical and microanatomical data from prenatal normal and dysmorphic modern humans will be compared to mouse ontogenetic patterns. By performing within-species analyses, this project will uniquely investigate the cranial correlates of brain enlargement during fetal development and, ultimately, human evolution. This project will have the broader impact of incorporating highly diverse data and cutting-edge methods in order to significantly increase our knowledge of cranial integration, prenatal development, and the evolution of encephalization. This represents the first step in a research program aimed at unraveling prenatal and postnatal determinants of human skull form.

在灵长类动物进化过程中的一些重大事件，以及灵长类动物的发展，都以相对大脑大小的大幅增加为标志。 事实上，包括现代人类在内的许多灵长类动物的起源都以大脑和头骨的惊人变化为特征。 虽然大脑的扩张一直被认为会影响头骨的形状，有一个种间和种内的结果之间的差异很大，哪些因素差异影响灵长类动物头骨的组织。 这削弱了我们对现存和灭绝的灵长类动物头骨形状的主要决定因素的理解。 为了纠正这一缺陷，拟议的分析使用新的样本和技术来检验这一假设，即颅底和穹窿形状的变化与大脑大小的变化显著相关。 为了解决人类大脑进化和胎儿生长的实验模型的稀缺性，表达稳定形式的β-连环蛋白的转基因小鼠将用于分离相对大脑大小对颅底和穹窿的发育和形态的影响。 由于神经前体细胞的增加，这些小鼠发育出高度增大的脑，并且由于β-连环蛋白转基因仅在此类脑细胞中表达，因此预测野生型和转基因同窝出生小鼠之间的颅骨形状差异仅由脑大小和形状的差异引起。 通过专注于产前时期，其特点是显着的大脑生长，这个项目将有利于我们的理解一个至关重要的时期，当主要的结构和功能的相互关系建立在头骨。 特别是，这些数据将是重要的灵长类动物的头骨形态的演变，以及正常和病理性的头骨发育在人类的基础研究，以检查产前组织的头骨，转基因小鼠将分析在几个阶段的发展，使用磁共振成像（MRI），微计算机断层扫描（microCT），三维几何形态测量学，组织学和免疫组织化学。 将来自产前正常和畸形现代人的三维宏观解剖和微观解剖数据与小鼠个体发育模式进行比较。 通过进行物种内分析，该项目将独特地研究胎儿发育过程中大脑扩大的颅骨相关性，并最终研究人类进化。 该项目将具有更广泛的影响，包括高度多样化的数据和尖端的方法，以显着增加我们对颅整合，产前发育和脑化演变的了解。 这是一项旨在揭示人类头骨形状的产前和产后决定因素的研究计划的第一步。