Mapping neural stem cells in periventricular heterotopia

Merino, Florencia Lucia (2024): Mapping neural stem cells in periventricular heterotopia. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Neurological disorders pose a substantial challenge to global healthcare, profoundly affecting individuals, their families, and communities at large. The rising incidence of these disorders requires effective intervention strategies, emphasizing the critical need to understand brain function and development for a deeper insight into their etiology. This thesis delves into the complex mechanisms of brain development, particularly focusing on a brain disorder known as periventricular heterotopia (PH). Periventricular heterotopia is characterized by groups of neurons ectopically localized below the brain cortex, often linked to epilepsy and cognitive impairment. Traditionally, heterotopias have been attributed to abnormal neuronal migration. However, recent studies are increasingly pointing to disrupted mechanisms in both progenitor cells and neurons as underlying factors in PH. Yet, the specific contribution of each cell type to the resulting ectopic phenotype has never been determined. Furthermore, it is still unclear why only some cells are affected in this condition, while the majority of other cortical cells can successfully reach their cortical position. This thesis aims to help the understanding of these important questions. In the first study comprising this thesis, a characterization of the centrosome’s composition in both neural stem cells and neurons was performed, revealing that centrosome-associated proteins are largely cell-type specific. Relevantly, overlaying the interactomes with genetic variants from patients with distinct neurodevelopmental disorders identified a significant enrichment of genes associated with PH within the NSC centrosome proteome. Consequently, the first aim of this thesis was to study the functional implications of PRPF6, a protein enriched in neural stem cell’s centrosome and linked with PH, in cortical development. Here, we explored which cell types are affected upon PRPF6 manipulation, which are responsible for the resulting phenotype, and whether we can distinguish the different cellular processes mediating it. Answers to these questions are addressed in chapter 3.1, which includes a manuscript published in Science in 2022. Furthermore, a follow-up study explores whether unidentified functions of PH-associated genes could further contribute to their apparent lack of interrelation. In this context, the second aim of this thesis was to conduct a comprehensive study on the role of the PH-associated gene Map1b in the mouse developing cortex. In particular, we explored whether Map1b manipulation can alter neuronal development, its potential yet unrecognized role in neural stem cells, and whether, as in PH patients, a neuronal particularly vulnerable subpopulation could be identified, resulting in the exploration of its origin. These questions are discussed in a manuscript included in chapter 3.2. In summary, this thesis represents a comprehensive exploration of the impact of PH-associated proteins in neuronal development, particularly highlighting their significance in the disease etiology. Our results underscore the crucial role of early neuronal differentiation defects in what has traditionally been considered a disorder of neuronal migration. Moreover, the included studies highlight the critical role of moonlighting proteins in cortical development. By observing the dual functions of proteins like MAP1B in neuronal migration and neural stem cell’s differentiation and exploring the impact of PH-associated proteins present in neural stem cells centrosome, like PRPF6, this thesis challenges existing paradigms, and opens new avenues for future research, contributing to our understanding of the complex mechanisms underlying brain development and neuronal heterotopias.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Neurodevelopmental disorders, neural stem cells, periventricular heterotopia, neurogenesis, cortical development, radial glia cells
• Themengebiete: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 19. Dezember 2024
• 1. Bericht­erstatter:in: Götz, Magdalena