Regulation of cerebral cortex folding by controlling neuronal migration and progenitor expansion

Chun, Seung Hee (2024): Regulation of cerebral cortex folding by controlling neuronal migration and progenitor expansion. Dissertation, LMU München: Fakultät für Biologie

Abstract

Cerebral cortex folding represents a highly important evolutionary mechanism, one that remains, as yet, not fully understood. Present evidence suggests that cortex folding is caused by two cellular mechanisms: (1) expansion of progenitor cells, and (2) divergent radial migration of neurons. We previously generated a genetic deletion mouse model in which two cell adhesion molecules were ablated: Flrt1/Flrt3 double knockout mice. This model showed sulci-like cortex folding induced by divergent radial neuronal migration without expansion of progenitor cells. We used this ‘cell migration’ model to ask if the two folding mechanisms synergize, and whether the expansion of certain types of progenitors leads to qualitatively different cortical folds. In this thesis, I describe the generation and phenotypic analysis of two different triple knockout (TKO) mouse lines. I found that overproduction of intermediate progenitors by deletion of the centrosomal protein 83 (Cep83) in this ‘cell migration’ model (Cep83/Flrt1/Flrt3TKO mice, in short Cep83TKO mice) lead to cortical folding with an increased sulci-like appearance. In a separate mouse model, increasing the length of the early cortical stem cell expansion phase by deletion of fibroblast growth factor 10 (FGF10) in the ‘cell migration’ model (Fgf10/Flrt1/Flrt3TKO mice, in short Fgf10TKO mice) lead to cortical folding with a much increased penetrance and, interestingly, gyrus-like protrusions. These results indicate that expansion of progenitor cells and divergent radial migration of neurons synergize in vivo to induce cortical folding. They further suggest that expanding different types of progenitors leads to qualitatively different folding, raising the possibility that the formation of gyri and sulci requires the timely expansion of distinct progenitors.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: cortical folding, sulcus, gyrus, migration, cell proliferation
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 23. Januar 2024
• 1. Bericht­erstatter:in: Klein, Rüdiger