Profilin 1 and profilin 2-dependent actin dynamics shape neuronal morphology and are involved in brain development
Profilin 1 and profilin 2-dependent actin dynamics shape neuronal morphology and are involved in brain development
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DissertationPrüfungsdatum
20.10.2022Datum der Veröffentlichung
27.09.2023Erstgutachter
Witke, WalterZweitgutachter
Stein, ValentinMetadaten
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Inhalt
The actin cytoskeleton is an important structure at the synaptic terminals and controls key parameters in synaptic physiology and plasticity. Actin binding proteins (ABPs) regulate cytoskeletal remodeling and actin dynamics at the synapse affecting synaptic transmission. Among all the different ABPs, profilin 1 (PFN1) and profilin 2 (PFN2) are part of a family of proteins that bind monomeric actin and promote filament polymerization. It has been previously shown that the mouse model lacking PFN2 exhibits an alteration of synaptic activity, due to increased excitability of glutamatergic transmission in the cortico-striatal pathway, while the mouse model lacking PFN1 in the brain displays mild neuronal migration defects but no synaptic function alterations.
In the first part of this thesis are reported evidences suggesting that Pfn2 loss in mice produces an autistic-like behavior, caused by an imbalanced glutamatergic/GABAergic transmission in the Schaffer collaterals. The maintenance of the excitation-inhibition balance is critical for normal brain development and for its regular functioning.
In the second part of the thesis, studies on Pfn1;Pfn2 double knockout mouse lines were performed at both developmental and adult age in order to properly dissect the specific and redundant functions of the two profilin isoforms. PFN1 appears most relevant for patterning brain structures during early development of the CNS and, for the first time, PFN2-redundant functions are also uncovered. Moreover, the function of profilins, especially PFN1, in regulating cell cycle progression supports the existence of an actin cytoskeleton checkpoint preceding phase G2/M transition of the cell cycle.
In the adult brain both profilins are necessary for the maintenance of dendritic complexity of cortical and hippocampal pyramidal neurons. Since PFN2 is higher expressed compared to PFN1, PFN2 loss has higher impact on neuronal structural integrity. In conclusion, this work shows that PFN1 and PFN2 play different functions in the developing and adult brain.
In the first part of this thesis are reported evidences suggesting that Pfn2 loss in mice produces an autistic-like behavior, caused by an imbalanced glutamatergic/GABAergic transmission in the Schaffer collaterals. The maintenance of the excitation-inhibition balance is critical for normal brain development and for its regular functioning.
In the second part of the thesis, studies on Pfn1;Pfn2 double knockout mouse lines were performed at both developmental and adult age in order to properly dissect the specific and redundant functions of the two profilin isoforms. PFN1 appears most relevant for patterning brain structures during early development of the CNS and, for the first time, PFN2-redundant functions are also uncovered. Moreover, the function of profilins, especially PFN1, in regulating cell cycle progression supports the existence of an actin cytoskeleton checkpoint preceding phase G2/M transition of the cell cycle.
In the adult brain both profilins are necessary for the maintenance of dendritic complexity of cortical and hippocampal pyramidal neurons. Since PFN2 is higher expressed compared to PFN1, PFN2 loss has higher impact on neuronal structural integrity. In conclusion, this work shows that PFN1 and PFN2 play different functions in the developing and adult brain.
Schlagwörter
Aktin, Profiline, Autismus, Entwicklung, Gehirn, Actin, profilins, autism, development, brain
Klassifikation (DDC)
570 Biowissenschaften, BiologieZugehörige Publikation(en)
https://doi.org/10.3390/cells10092310Di Domenico, Marina: Profilin 1 and profilin 2-dependent actin dynamics shape neuronal morphology and are involved in brain development. - Bonn, 2023. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-72480
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-72480
@phdthesis{handle:20.500.11811/11071,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-72480,
author = {{Marina Di Domenico}},
title = {Profilin 1 and profilin 2-dependent actin dynamics shape neuronal morphology and are involved in brain development},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2023,
month = sep,
note = {The actin cytoskeleton is an important structure at the synaptic terminals and controls key parameters in synaptic physiology and plasticity. Actin binding proteins (ABPs) regulate cytoskeletal remodeling and actin dynamics at the synapse affecting synaptic transmission. Among all the different ABPs, profilin 1 (PFN1) and profilin 2 (PFN2) are part of a family of proteins that bind monomeric actin and promote filament polymerization. It has been previously shown that the mouse model lacking PFN2 exhibits an alteration of synaptic activity, due to increased excitability of glutamatergic transmission in the cortico-striatal pathway, while the mouse model lacking PFN1 in the brain displays mild neuronal migration defects but no synaptic function alterations.
In the first part of this thesis are reported evidences suggesting that Pfn2 loss in mice produces an autistic-like behavior, caused by an imbalanced glutamatergic/GABAergic transmission in the Schaffer collaterals. The maintenance of the excitation-inhibition balance is critical for normal brain development and for its regular functioning.
In the second part of the thesis, studies on Pfn1;Pfn2 double knockout mouse lines were performed at both developmental and adult age in order to properly dissect the specific and redundant functions of the two profilin isoforms. PFN1 appears most relevant for patterning brain structures during early development of the CNS and, for the first time, PFN2-redundant functions are also uncovered. Moreover, the function of profilins, especially PFN1, in regulating cell cycle progression supports the existence of an actin cytoskeleton checkpoint preceding phase G2/M transition of the cell cycle.
In the adult brain both profilins are necessary for the maintenance of dendritic complexity of cortical and hippocampal pyramidal neurons. Since PFN2 is higher expressed compared to PFN1, PFN2 loss has higher impact on neuronal structural integrity. In conclusion, this work shows that PFN1 and PFN2 play different functions in the developing and adult brain.},
url = {https://hdl.handle.net/20.500.11811/11071}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-72480,
author = {{Marina Di Domenico}},
title = {Profilin 1 and profilin 2-dependent actin dynamics shape neuronal morphology and are involved in brain development},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2023,
month = sep,
note = {The actin cytoskeleton is an important structure at the synaptic terminals and controls key parameters in synaptic physiology and plasticity. Actin binding proteins (ABPs) regulate cytoskeletal remodeling and actin dynamics at the synapse affecting synaptic transmission. Among all the different ABPs, profilin 1 (PFN1) and profilin 2 (PFN2) are part of a family of proteins that bind monomeric actin and promote filament polymerization. It has been previously shown that the mouse model lacking PFN2 exhibits an alteration of synaptic activity, due to increased excitability of glutamatergic transmission in the cortico-striatal pathway, while the mouse model lacking PFN1 in the brain displays mild neuronal migration defects but no synaptic function alterations.
In the first part of this thesis are reported evidences suggesting that Pfn2 loss in mice produces an autistic-like behavior, caused by an imbalanced glutamatergic/GABAergic transmission in the Schaffer collaterals. The maintenance of the excitation-inhibition balance is critical for normal brain development and for its regular functioning.
In the second part of the thesis, studies on Pfn1;Pfn2 double knockout mouse lines were performed at both developmental and adult age in order to properly dissect the specific and redundant functions of the two profilin isoforms. PFN1 appears most relevant for patterning brain structures during early development of the CNS and, for the first time, PFN2-redundant functions are also uncovered. Moreover, the function of profilins, especially PFN1, in regulating cell cycle progression supports the existence of an actin cytoskeleton checkpoint preceding phase G2/M transition of the cell cycle.
In the adult brain both profilins are necessary for the maintenance of dendritic complexity of cortical and hippocampal pyramidal neurons. Since PFN2 is higher expressed compared to PFN1, PFN2 loss has higher impact on neuronal structural integrity. In conclusion, this work shows that PFN1 and PFN2 play different functions in the developing and adult brain.},
url = {https://hdl.handle.net/20.500.11811/11071}
}
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