My doctoral research focused on investigating forebrain development in gene-disruption models with altered RAC1 GTPase pathway activity. Specifically, I studied the effects of mutations in two key regulatory proteins of RAC1 GTPase, ARHGAP15 and ARHGEF6, on neurogenesis, migration, and differentiation dynamics. The second chapter presents the results of a study aimed at investigating the effects of Arhgap15 ablation, a gene encoding a specific negative regulator of RAC1, on the migration and maturation of cortical GABAergic INs (CINs) during mouse development. This study revealed that ARHGAP15 exerts a nuanced negative regulation on RAC1-dependent cytoskeletal remodeling, crucial for morphological maturation and directional control during CIN migration, ultimately influencing their laminar distribution and inhibitory function (Liaci et al., 2022) . Chapter 3 delves into the role of ARHGEF6, a positive regulator of RAC1, in both mouse and human forebrain development. Mutations in ARHGEF6 are causally linked to non-syndromic intellectual disability (ID) MRX46 (OMIM: 300436). The study showed that Arhgef6-KO mice exhibit a significant reduction in hippocampal GABAergic INs (INs), particularly in the CA2 and CA3 regions, along with impairments in IN maturation. To explore the human context, we generated ARHGEF6-KO human induced pluripotent stem cells (hiPSCs). hiPSC-derived ventral organoids were utilized to assess alterations in ARHGEF6-KO related to cell proliferation, differentiation, and survival. Studies on dorsal-ventral assembloids demonstrated that ARHGEF6-KO INs exhibit a distinct migration phenotype, contributing to the reduction of the number of INs reaching the dorsal compartment. Overall, these results suggest that the observed defects in the number of GABAergic INs at the hippocampal level may arise from three primary factors: impaired progenitor proliferation and differentiation capacity, decreased survival, and migration defects. Collectively, these findings reinforce the previously established link in the literature between ID and alterations in forebrain GABAergic system development. Our data further highlight the critical role of the RAC1 pathway in regulating the proliferation, differentiation, and migration of progenitors and INs.

The Role of the RAC1-Regulating Proteins ARHGAP15 and ARHGEF6 in the Development of Forebrain GABAergic INs(2024 Dec 17).

The Role of the RAC1-Regulating Proteins ARHGAP15 and ARHGEF6 in the Development of Forebrain GABAergic INs

LIACI, CARLA
2024-12-17

Abstract

My doctoral research focused on investigating forebrain development in gene-disruption models with altered RAC1 GTPase pathway activity. Specifically, I studied the effects of mutations in two key regulatory proteins of RAC1 GTPase, ARHGAP15 and ARHGEF6, on neurogenesis, migration, and differentiation dynamics. The second chapter presents the results of a study aimed at investigating the effects of Arhgap15 ablation, a gene encoding a specific negative regulator of RAC1, on the migration and maturation of cortical GABAergic INs (CINs) during mouse development. This study revealed that ARHGAP15 exerts a nuanced negative regulation on RAC1-dependent cytoskeletal remodeling, crucial for morphological maturation and directional control during CIN migration, ultimately influencing their laminar distribution and inhibitory function (Liaci et al., 2022) . Chapter 3 delves into the role of ARHGEF6, a positive regulator of RAC1, in both mouse and human forebrain development. Mutations in ARHGEF6 are causally linked to non-syndromic intellectual disability (ID) MRX46 (OMIM: 300436). The study showed that Arhgef6-KO mice exhibit a significant reduction in hippocampal GABAergic INs (INs), particularly in the CA2 and CA3 regions, along with impairments in IN maturation. To explore the human context, we generated ARHGEF6-KO human induced pluripotent stem cells (hiPSCs). hiPSC-derived ventral organoids were utilized to assess alterations in ARHGEF6-KO related to cell proliferation, differentiation, and survival. Studies on dorsal-ventral assembloids demonstrated that ARHGEF6-KO INs exhibit a distinct migration phenotype, contributing to the reduction of the number of INs reaching the dorsal compartment. Overall, these results suggest that the observed defects in the number of GABAergic INs at the hippocampal level may arise from three primary factors: impaired progenitor proliferation and differentiation capacity, decreased survival, and migration defects. Collectively, these findings reinforce the previously established link in the literature between ID and alterations in forebrain GABAergic system development. Our data further highlight the critical role of the RAC1 pathway in regulating the proliferation, differentiation, and migration of progenitors and INs.
17-dic-2024
36
MEDICINA MOLECOLARE
MERLO, Giorgio Roberto
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/2042990
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