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

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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.