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Generation of Authentic Human Neocortical Neurons from Induced Pluripotent Stem Cells to Investigate 7Q11.23 Gene Dosage Imbalances

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Generation of Authentic Human Neocortical Neurons from Induced Pluripotent Stem Cells to Investigate 7Q11.23 Gene Dosage Imbalances UNIVERSITA’ DEGLI STUDI DI MILANO PhD Course in Molecular and Cellular Biology XXIX Ciclo Generation of authentic human neocortical neurons from induced pluripotent stem cells to investigate 7q11.23 gene dosage imbalances Alice Maria Giani PhD Thesis Scientific tutors: Prof. Nenad Sestan Prof. Marco Muzi Falconi Academic year: 2016-2017 SSD: BIO/11 Thesis performed at:iiDepartment of Biosciences University of Milan, Milano 20133, Italy Department of Neuroscience Yale University, New Haven 06510, CT (US) 2 CONTENTS Acknowledgements PART I: Introduction 1 Abstract 2 Chapter 1: Human neocortical development 1.1 Structural organization of the human postnatal cerebral cortex 3 1.2 Neurons of the cerebral cortex 4 1.3 Neocortical neurogenesis 7 1.4 Neocortical migration 10 1.5 Signaling pathways regulating neocortical development 13 1.6 Transcriptional programs orchestrating neocortical development 26 Chapter 2: Pluripotent stem cells 2.1 Pluripotent stem cells 28 2.2 Induced pluripotent stem cells 30 2.3 Pluripotent stem cells as a tool to investigate human neocortical development in health and disease 36 Chapter 3: Genetic basis of neurodevelopmental disorders 3.1 Genetic architecture of neurodevelopmental disorders 39 3.2 Copy number variations contribution to neurodevelopmental disorders liability 41 3.3 Copy number variation at the 7q11.23 locus 43 3.4 Williams syndrome 45 3.5 7q11.23 duplication syndrome 47 3.6 Analysis of the genotype-phenotype correlation in Williams syndrome and 7q11.23 duplication syndrome 48 3 PART II: Results 50 Chapter 4: Induced pluripotent stem cells as a model system to investigate human neocortical development in health and disease 4.1 Derivation of human induced pluripotent stem cell lines 51 4.2 Pluripotency validation of human induced pluripotent stem cell lines 54 Chapter 5: Extensive characterization of a human pluripotent stem cells based differentiation protocol for the in vitro generation of authentic neocortical neurons 5.1 Pluripotent stem cells based directed neocortical differentiation protocol 58 5.2 Integrative analysis of iPSCs-derived neuronal populations obtained at different in vitro neurodevelopmental stages 60 5.2.1 Transcriptional analysis of human induced pluripotent stem cells- derived neuronal cells 61 5.2.2 Transcriptional analysis of human induced pluripotent stem cells- derived neuronal cells at single cell level 76 5.2.3 Immunocytochemical validation of neuronal cell types identities 85 5.2.4 Functional properties of iPSCs-derived neocortical neurons 90 Chapter 6: Human neocortical neurons derived from induced pluripotent stem cells to investigate the effects of 7q11.23 gene- dosage dysregulation 6.1 Integrated co-expression and PPI analyses identify three 7q11.23 gene clusters with distinct functions 98 6.2 Spatiotemporal expression and cellular localization of DNAJC30 105 6. 3 Immunocytochemical validation of iPSCs-derived neocortical neurons to investigate 7q11.23 dosage-dependent dysregulation 108 6.4 Morphological analysis of iPSCs-derived neocortical neurons from Williams syndrome patients and healthy subjects 110 Discussion 114 4 PART III 123 Materials and Methods 124 References 139 5 Acknowledgements I would like to express my sincere gratitude to my thesis advisor Professor Nenad Sestan (Yale University) and Professor Muzi-Falconi (University of Milan) for their support and guidance in science and scientific career development accompanied by a constant encouragement in pursuing new ideas with independence and envisioning scientific questions with creativity. I would like to thank Professor Elena Cattaneo (University of Milan) for having offered me the opportunity to join her laboratory in the first rotation of my graduate studies and having introduced me to the stem cell filed and Professor Graziella Messina (University of Milan) for her valuable project advices in her role of third supervisor and for having offered me the possibility to enrich and broaden my background in the stem cells of different lineages during the second rotation in her laboratory. I would like to thank all members of Sestan laboratory for their intellectual support and constructive scientific exchanges. In particular, I wish to thank Candace Bichsel for having been a mentor and having accompanied me in the journey of reaching scientific independence with constant encouragement and support and serving as an example. I would like to thank Andrew Tebbenkamp for the constructive collaboration and valuable advices in elaborating the study design of the project aimed to investigate the effects of 7q11.23 gene-dosage dysregulation, Zhen Li and Tianliuyun Gao for sharing their expertise in single cell RNA-sequencing and the other members of the laboratory stem cell team Marco Onorati and Fuchen Liu for their productive collaboration and feedbacks. I wish to thank also Mingfeng Li, Zhen Li, Gabriel Santpere, Belen Lorente- Galdos, Kyle Meyer and Ying Zhu for collaboration and discussion on data analysis and Francesca Talpo (University of Pavia) for contributing her precious expertise in electrophysiology. I would also like to thank all members of Elena Cattaneo and Graziella Messina laboratories with whom I had the pleasure to collaborate and work side by side for providing a wonderful scientific environment. My special thanks goes to my loving family and true friends to whom this dissertation is dedicated. Part I: Introduction Part I: Introduction 1 Part I: Introduction Abstract This research project has been aimed to investigate human neocortical development in healthy and diseased subjects by analyzing and comparing the transcriptional profiles and cellular morphologies of human neocortical cells derived from induced pluripotent stem cells (iPSCs). Given the importance to rely on a solid and highly reproducible iPSCs-based differentiation protocol that generates authentic neocortical neurons in vitro with high efficiency before applying it as a model system of human neurodevelopmental disorders, in the first phase of this study we performed a comprehensive transcriptional, cellular and physiological characterization of the in vitro neurodevelopmental paradigm. The transcriptional dynamics regulating in vitro neocortical development have been investigated by performing RNA-sequencing (RNA-seq) at both population and single- cell level in combination with several bioinformatics analyses including principal component analysis (PCA), differential gene expression analysis and weighted gene co- expression network analysis (WGCNA). The transcriptional results were corroborated by the widespread positivity for a selected panel of informative cell-fate and cell-stage specific markers detected through immunocytochemistry and the physiological maturity of our iPSCs-derived neocortical neurons was further confirmed by their ability to generate action potentials, develop complex firing patterns and sustain excitatory and inhibitory spontaneous synaptic activity. Overall, these results fully validated the reproducibility of the differentiation protocol and its efficiency and reliability in generating physiologically mature authentic neocortical neurons. Subsequently, we applied this extensively characterized neocortical differentiation paradigm to model in vitro two human neurodevelopmental disorders caused by symmetrical copy number variations (CNVs) of the Williams-Beuren syndrome chromosome region (WBSCR) located on the long arm (q) of chromosome 7 at position 11.23 (7q.11.23 locus). 7q11.23 CNVs are of special interest as the two disorders resulting from the deletion (Williams syndrome, WS) and duplication (7q.11.23 duplication syndrome, 7q11DUP) of this region exhibit cognitive and behavioral phenotypes marked by both similar features and symmetrically opposite traits. The association of 7q11DUP to complex neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, while WS is a well-characterized syndrome without clear overlap to complex neurodevelopmental disorders make the study of this locus extremely interesting to identify the molecular mechanisms unique to each clinical condition, common to both syndromes and shared with other complex neurodevelopmental disorders. To this aim, we generated several iPSCs lines from a large cohort comprising WS individuals, 7q11DUP patients and healthy subjects and differentiated them into neocortical neurons by applying the previously in-depth characterized protocol. Having assessed the quality of our iPSCs-derived neocortical neurons, we are currently identifying neuronal subtypes specific genes and gene networks having the most statistically significant relationship to these disorders through single cell RNA-sequencing analysis. Furthermore, morphometric analysis of WS and control iPSCs-derived neocortical neurons has confirmed in humans many neuronal morphological abnormalities observed in a mouse knockout for Dnajc30, a previously uncharacterized gene contained in the 7q11.23 locus. 2 Part I: Introduction Chapter 1: Human neocortical development 1.1 Structural organization of the human postnatal cerebral cortex The human cerebral cortex, also known as neocortex, is a 1-4.5 mm thick mantle of gray matter constituting the outermost surface of the cerebral hemispheres enclosing the underlying white matter [1]. The gray matter is composed of a tightly packed network of different neurons supported by a diverse range of glial cells and capillaries that constitutes up to 80% of the brain mass [2], while the white matter consists of the myelinated
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