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

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育，都以相对大脑大小的显著增加为标志。事实上，包括现代人类在内的许多灵长类动物群体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形状，但关于哪些因素会影响灵长类动物头骨的组织，种间和种内的研究结果存在很大差异。这削弱了我们对现存和已灭绝灵长类动物头骨形状的主要决定因素的理解。为了纠正这一缺点，提出的分析使用新的样本和技术来检验颅基底和拱顶形状的变化与脑大小的变化显著相关的假设。为了解决人类大脑进化和胎儿生长实验模型的缺乏，将使用表达稳定形式的β -catenin蛋白的转基因小鼠来分离相对脑大小对颅底和拱顶发育和形态的影响。由于神经前体细胞的增加，这些小鼠的大脑发育高度增大，由于β -连环蛋白转基因仅在这些脑细胞中表达，因此野生型和转基因幼崽之间头骨形状的差异预计仅由大脑大小和形状的差异引起。通过关注以大脑显著发育为特征的产前时期，该项目将有助于我们了解颅骨内主要结构和功能相互关系建立的关键重要时期。特别是，这些数据对于理解灵长类动物颅骨形态的进化以及对人类正常和病理颅骨发育的基础转化研究至关重要。为了检查颅骨的产前组织，转基因小鼠将在发育的几个阶段使用磁共振成像（MRI）、微计算机断层扫描（microCT）、3D几何形态计量学、组织学和免疫组织化学进行分析。产前正常和畸形现代人的三维宏观解剖和微观解剖数据将与小鼠个体发生模式进行比较。通过进行物种内分析，该项目将独特地研究胎儿发育期间大脑扩大的颅骨相关性，并最终研究人类进化。这个项目将有更广泛的影响，将高度多样化的数据和尖端的方法结合起来，以显著增加我们对颅骨整合、产前发育和脑化进化的认识。这代表了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。

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.