The role of the transcription factor BCL11A in midbrain dopaminergic neurons
The role of the transcription factor BCL11A in midbrain dopaminergic neurons
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DissertationDate of Exam
11.02.2022Date of Publication
11.03.2022Advisor
Blaess, SandraCo-Referee
Witke, WalterMetadata
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Abstract
Midbrain dopaminergic (mDA) neurons are located in three midbrain nuclei, the substantia nigra (SN), ventral tegmental area (VTA) and retrorubral field (RRF). mDA neurons are diverse in their developmental origin, their gene expression, their projection targets, their electrophysiological and functional properties, their ability to co-release other neurotransmitters together with dopamine and their vulnerability to neurodegeneration. Little is known about the molecular mechanisms that establish this diversity in mDA neurons during development.
Diverse cellular programs have to be executed and maintained during differentiation and maturation to establish mDA neurons with distinct projections and functions. Transcription factors are known to direct these cellular differentiation programs. In this study the expression of a zinc finger transcription factor, BCL11A (B-cell lymphoma 11a), has been characterized in both the developing and adult murine brain, to examine whether BCL11A is expressed in a subset of mDA neurons. To explore whether BCL11A-expressing mDA neurons form a highly specific subcircuits within the dopaminergic (DA) system, intersectional fate mapping, anterograde viral mediated tracing and retrograde tracing approaches were combined. To investigate whether BCL11A is necessary for establishing and/or maintaining BCL11A-expressing mDA neurons and their cell fate, a conditional knock-out mouse model for BCL11A in mDA neurons was generated. A set of behavioural experiments was carried out to assess whether the loss of BCL11A leads to functional impairment in the mDA system, Moreover, to elucidate the role of BCL11A expression in the context of neuronal challenges and neurodegenerative processes affecting mDA neurons in the SN, mDA neurons were challenged with a-synuclein overexpression.
The results of this study reveal that BCL11A is expressed in about a third of mDA neurons in the SN, VTA and RRF and that BCL11A-expressing mDA neurons contribute to several known subpopulations of mDA neurons. Intersectional labelling and tracing experiments show that BCL11A-expressing mDA neurons, despite their broad anatomical distribution, form a highly specific subcircuit within the DA system. BCL11A specific inactivation in mDA neurons led to changes in the anatomical positioning of BCL11A-expressing mDA neurons. Moreover, mice lacking BCL11A expression in mDA neurons show deficiencies in motor learning, suggesting that loss of BCL11A results in a functional impairment of mDA neurons. Furthermore, by challenging mDA neurons with a-synuclein overexpression, a model of Parkinson’s disease, BCL11A-expressing SN neurons have been shown to be particularly vulnerable to neurodegeneration. Additionally, the loss of BCL11A in this population increases their susceptibility to a-synuclein-induced degeneration.
This study links the developmental origin of a specific subset of mDA neurons to their vulnerability phenotype and functional and circuit specialization. Thus, the results of this study demonstrate that a better understanding of the genetically defined developmental history of mDA neurons is instrumental to understand the functional organization of the DA system and its susceptibility to neurodegeneration in the adult brain. Dopaminerge Neuronen des Mittelhirns (mDA) befinden sich in drei Kerngebieten des Mittelhirns, der Substantia nigra (SN), dem ventralen tegmentalen Areal (VTA) und dem retrorubralen Feld (RRF). mDA-Neurone unterscheiden sich in ihrem entwicklungsbedingten Ursprung, ihrer Genexpression, ihren Projektionszielen, ihren elektrophysiologischen und funktionellen Eigenschaften, ihrer Fähigkeit, andere Neurotransmitter zusammen mit Dopaminfreizusetzen und ihrer Anfälligkeit für Neurodegeneration. Über die molekularen Mechanismen, die diese Vielfalt in mDA-Neurone während der Entwicklung etablieren, ist jedoch wenig bekannt.
Diverse zelluläre Programme müssen während der Differenzierung und Reifung ausgeführt und aufrechterhalten werden, um mDA-Neuronen mit unterschiedlichen Projektionen und Funktionen zu etablieren. Transkriptionsfaktoren sind dafür bekannt, diese zellulären Differenzierungsprogramme zu steuern. In dieser Studie wurde die Expression eines Zinkfinger-Transkriptionsfaktors, BCL11A (B-Zell-Lymphom 11a), sowohl im sich entwickelnden als auch im adulten murinen Gehirn charakterisiert, um zu untersuchen, ob BCL11A in einer Untergruppe von mDA-Neuronen exprimiert wird. Und um zu beurteilen, ob BCL11A-positive mDA-Neuronen zu mehreren bekannten Subpopulationen von mDA-Neuronen gehören, wurden immunhistochemiesche Experimente sowohl im neonatalen als auch im adulten murinen Mittelhirndurchgeführt. Um zu untersuchen, ob BCL11A-exprimierende mDA-Neuronen Teil eines spezifischen Netzwerks innerhalb des dopaminergen Systems bilden, wurden intersektionales Fate Mapping, anterogrades virenvermitteltes Tracing und retrograde Tracing-Ansätze kombiniert. Um zu ermitteln, ob BCL11A für die Etablierung und/oder Aufrechterhaltung von BCL11A-exprimierendenmDA-Neuronen und deren Zellschicksal notwendig ist, wurde ein konditionales Knock-out Mausmodell für BCL11A in mDA-Neuronen erzeugt. Es wurden eine Reihe Verhaltensexperimente durchgeführt um zu untersuchen ob der Verlust von BCL11Azu einer funktionellen Beeinträchtigung im mDA System führt. Letztendlich wurde die Anfälligkeit von BCL11A exprimierenden mDA-Neuronen auf neurodegenerative Prozesse durch die Überexpression von a-Synuclein getestet.
Die Ergebnisse dieser Studie zeigen, dass BCL11A in etwa einem Drittel der mDA-Neuronen in der SN, VTA und dem RRF exprimiert wird und dass BCL11A-exprimierende mDA-Neurone zu mehreren bekannten Subpopulationen von mDA-Neuronen beitragen. Intersektionelle Markierungs- und Tracing-Experimente zeigen, dass BCL11A-exprimierende mDA-Neurone, trotzihrer breiten anatomischen Verteilung, einen hochspezifischen Teil desneuronalen Netzwerks innerhalb des dopaminergen Systems bilden. Die spezifische Inaktivierung von BCL11A in mDA-Neuronen führte zu anatomischen Veränderungen in der Positionierung der BCL11A-positiven mDA-Neurone. Darüber hinaus zeigen Mäuse, denen die BCL11A-Expression in mDA-Neuronen fehlt, Defizite beim motorischen Lernen, was darauf hindeutet, dass der Verlust von BCL11A zu einer funktionellen Beeinträchtigung von mDA-Neuronen führt. Außerdem wurde durch eine Überexpression von a-Synuclein in mDA-Neuronen, einem Modell der Parkinson-Erkrankung, gezeigt, dass BCL11A-exprimierende SN-Neurone besonders anfällig für Neurodegeneration sind. Zusätzlich erhöht der Verlust von BCL11A in dieser Population ihre Anfälligkeit für eine a-Synuclein-induzierte Degeneration.
Diese Studie verbindet den entwicklungsbedingten Ursprungeiner spezifischen Untergruppe von mDA-Neuronen mit ihrem Vulnerabilitätsphänotyp und ihrer funktionellen und schaltungstechnischen Spezialisierung. Somit zeigen die Ergebnisse dieser Studie, dass ein besseres Verständnis der genetisch definierten Entwicklungsgeschichte von mDA-Neuronen entscheidend ist, um die funktionelle Organisation des dopaminergen Systems und seine Anfälligkeit für Neurodegeneration im erwachsenen Gehirn zu verstehen.
Diverse cellular programs have to be executed and maintained during differentiation and maturation to establish mDA neurons with distinct projections and functions. Transcription factors are known to direct these cellular differentiation programs. In this study the expression of a zinc finger transcription factor, BCL11A (B-cell lymphoma 11a), has been characterized in both the developing and adult murine brain, to examine whether BCL11A is expressed in a subset of mDA neurons. To explore whether BCL11A-expressing mDA neurons form a highly specific subcircuits within the dopaminergic (DA) system, intersectional fate mapping, anterograde viral mediated tracing and retrograde tracing approaches were combined. To investigate whether BCL11A is necessary for establishing and/or maintaining BCL11A-expressing mDA neurons and their cell fate, a conditional knock-out mouse model for BCL11A in mDA neurons was generated. A set of behavioural experiments was carried out to assess whether the loss of BCL11A leads to functional impairment in the mDA system, Moreover, to elucidate the role of BCL11A expression in the context of neuronal challenges and neurodegenerative processes affecting mDA neurons in the SN, mDA neurons were challenged with a-synuclein overexpression.
The results of this study reveal that BCL11A is expressed in about a third of mDA neurons in the SN, VTA and RRF and that BCL11A-expressing mDA neurons contribute to several known subpopulations of mDA neurons. Intersectional labelling and tracing experiments show that BCL11A-expressing mDA neurons, despite their broad anatomical distribution, form a highly specific subcircuit within the DA system. BCL11A specific inactivation in mDA neurons led to changes in the anatomical positioning of BCL11A-expressing mDA neurons. Moreover, mice lacking BCL11A expression in mDA neurons show deficiencies in motor learning, suggesting that loss of BCL11A results in a functional impairment of mDA neurons. Furthermore, by challenging mDA neurons with a-synuclein overexpression, a model of Parkinson’s disease, BCL11A-expressing SN neurons have been shown to be particularly vulnerable to neurodegeneration. Additionally, the loss of BCL11A in this population increases their susceptibility to a-synuclein-induced degeneration.
This study links the developmental origin of a specific subset of mDA neurons to their vulnerability phenotype and functional and circuit specialization. Thus, the results of this study demonstrate that a better understanding of the genetically defined developmental history of mDA neurons is instrumental to understand the functional organization of the DA system and its susceptibility to neurodegeneration in the adult brain.
Diverse zelluläre Programme müssen während der Differenzierung und Reifung ausgeführt und aufrechterhalten werden, um mDA-Neuronen mit unterschiedlichen Projektionen und Funktionen zu etablieren. Transkriptionsfaktoren sind dafür bekannt, diese zellulären Differenzierungsprogramme zu steuern. In dieser Studie wurde die Expression eines Zinkfinger-Transkriptionsfaktors, BCL11A (B-Zell-Lymphom 11a), sowohl im sich entwickelnden als auch im adulten murinen Gehirn charakterisiert, um zu untersuchen, ob BCL11A in einer Untergruppe von mDA-Neuronen exprimiert wird. Und um zu beurteilen, ob BCL11A-positive mDA-Neuronen zu mehreren bekannten Subpopulationen von mDA-Neuronen gehören, wurden immunhistochemiesche Experimente sowohl im neonatalen als auch im adulten murinen Mittelhirndurchgeführt. Um zu untersuchen, ob BCL11A-exprimierende mDA-Neuronen Teil eines spezifischen Netzwerks innerhalb des dopaminergen Systems bilden, wurden intersektionales Fate Mapping, anterogrades virenvermitteltes Tracing und retrograde Tracing-Ansätze kombiniert. Um zu ermitteln, ob BCL11A für die Etablierung und/oder Aufrechterhaltung von BCL11A-exprimierendenmDA-Neuronen und deren Zellschicksal notwendig ist, wurde ein konditionales Knock-out Mausmodell für BCL11A in mDA-Neuronen erzeugt. Es wurden eine Reihe Verhaltensexperimente durchgeführt um zu untersuchen ob der Verlust von BCL11Azu einer funktionellen Beeinträchtigung im mDA System führt. Letztendlich wurde die Anfälligkeit von BCL11A exprimierenden mDA-Neuronen auf neurodegenerative Prozesse durch die Überexpression von a-Synuclein getestet.
Die Ergebnisse dieser Studie zeigen, dass BCL11A in etwa einem Drittel der mDA-Neuronen in der SN, VTA und dem RRF exprimiert wird und dass BCL11A-exprimierende mDA-Neurone zu mehreren bekannten Subpopulationen von mDA-Neuronen beitragen. Intersektionelle Markierungs- und Tracing-Experimente zeigen, dass BCL11A-exprimierende mDA-Neurone, trotzihrer breiten anatomischen Verteilung, einen hochspezifischen Teil desneuronalen Netzwerks innerhalb des dopaminergen Systems bilden. Die spezifische Inaktivierung von BCL11A in mDA-Neuronen führte zu anatomischen Veränderungen in der Positionierung der BCL11A-positiven mDA-Neurone. Darüber hinaus zeigen Mäuse, denen die BCL11A-Expression in mDA-Neuronen fehlt, Defizite beim motorischen Lernen, was darauf hindeutet, dass der Verlust von BCL11A zu einer funktionellen Beeinträchtigung von mDA-Neuronen führt. Außerdem wurde durch eine Überexpression von a-Synuclein in mDA-Neuronen, einem Modell der Parkinson-Erkrankung, gezeigt, dass BCL11A-exprimierende SN-Neurone besonders anfällig für Neurodegeneration sind. Zusätzlich erhöht der Verlust von BCL11A in dieser Population ihre Anfälligkeit für eine a-Synuclein-induzierte Degeneration.
Diese Studie verbindet den entwicklungsbedingten Ursprungeiner spezifischen Untergruppe von mDA-Neuronen mit ihrem Vulnerabilitätsphänotyp und ihrer funktionellen und schaltungstechnischen Spezialisierung. Somit zeigen die Ergebnisse dieser Studie, dass ein besseres Verständnis der genetisch definierten Entwicklungsgeschichte von mDA-Neuronen entscheidend ist, um die funktionelle Organisation des dopaminergen Systems und seine Anfälligkeit für Neurodegeneration im erwachsenen Gehirn zu verstehen.
Classification (DDC)
500 Naturwissenschaften 570 Biowissenschaften, Biologie 610 Medizin, GesundheitTolve, Marianna: The role of the transcription factor BCL11A in midbrain dopaminergic neurons. - Bonn, 2022. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-65733
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-65733
@phdthesis{handle:20.500.11811/9670,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-65733,
author = {{Marianna Tolve}},
title = {The role of the transcription factor BCL11A in midbrain dopaminergic neurons},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2022,
month = mar,
note = {Midbrain dopaminergic (mDA) neurons are located in three midbrain nuclei, the substantia nigra (SN), ventral tegmental area (VTA) and retrorubral field (RRF). mDA neurons are diverse in their developmental origin, their gene expression, their projection targets, their electrophysiological and functional properties, their ability to co-release other neurotransmitters together with dopamine and their vulnerability to neurodegeneration. Little is known about the molecular mechanisms that establish this diversity in mDA neurons during development.
Diverse cellular programs have to be executed and maintained during differentiation and maturation to establish mDA neurons with distinct projections and functions. Transcription factors are known to direct these cellular differentiation programs. In this study the expression of a zinc finger transcription factor, BCL11A (B-cell lymphoma 11a), has been characterized in both the developing and adult murine brain, to examine whether BCL11A is expressed in a subset of mDA neurons. To explore whether BCL11A-expressing mDA neurons form a highly specific subcircuits within the dopaminergic (DA) system, intersectional fate mapping, anterograde viral mediated tracing and retrograde tracing approaches were combined. To investigate whether BCL11A is necessary for establishing and/or maintaining BCL11A-expressing mDA neurons and their cell fate, a conditional knock-out mouse model for BCL11A in mDA neurons was generated. A set of behavioural experiments was carried out to assess whether the loss of BCL11A leads to functional impairment in the mDA system, Moreover, to elucidate the role of BCL11A expression in the context of neuronal challenges and neurodegenerative processes affecting mDA neurons in the SN, mDA neurons were challenged with a-synuclein overexpression.
The results of this study reveal that BCL11A is expressed in about a third of mDA neurons in the SN, VTA and RRF and that BCL11A-expressing mDA neurons contribute to several known subpopulations of mDA neurons. Intersectional labelling and tracing experiments show that BCL11A-expressing mDA neurons, despite their broad anatomical distribution, form a highly specific subcircuit within the DA system. BCL11A specific inactivation in mDA neurons led to changes in the anatomical positioning of BCL11A-expressing mDA neurons. Moreover, mice lacking BCL11A expression in mDA neurons show deficiencies in motor learning, suggesting that loss of BCL11A results in a functional impairment of mDA neurons. Furthermore, by challenging mDA neurons with a-synuclein overexpression, a model of Parkinson’s disease, BCL11A-expressing SN neurons have been shown to be particularly vulnerable to neurodegeneration. Additionally, the loss of BCL11A in this population increases their susceptibility to a-synuclein-induced degeneration.
This study links the developmental origin of a specific subset of mDA neurons to their vulnerability phenotype and functional and circuit specialization. Thus, the results of this study demonstrate that a better understanding of the genetically defined developmental history of mDA neurons is instrumental to understand the functional organization of the DA system and its susceptibility to neurodegeneration in the adult brain.},
url = {https://hdl.handle.net/20.500.11811/9670}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-65733,
author = {{Marianna Tolve}},
title = {The role of the transcription factor BCL11A in midbrain dopaminergic neurons},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2022,
month = mar,
note = {Midbrain dopaminergic (mDA) neurons are located in three midbrain nuclei, the substantia nigra (SN), ventral tegmental area (VTA) and retrorubral field (RRF). mDA neurons are diverse in their developmental origin, their gene expression, their projection targets, their electrophysiological and functional properties, their ability to co-release other neurotransmitters together with dopamine and their vulnerability to neurodegeneration. Little is known about the molecular mechanisms that establish this diversity in mDA neurons during development.
Diverse cellular programs have to be executed and maintained during differentiation and maturation to establish mDA neurons with distinct projections and functions. Transcription factors are known to direct these cellular differentiation programs. In this study the expression of a zinc finger transcription factor, BCL11A (B-cell lymphoma 11a), has been characterized in both the developing and adult murine brain, to examine whether BCL11A is expressed in a subset of mDA neurons. To explore whether BCL11A-expressing mDA neurons form a highly specific subcircuits within the dopaminergic (DA) system, intersectional fate mapping, anterograde viral mediated tracing and retrograde tracing approaches were combined. To investigate whether BCL11A is necessary for establishing and/or maintaining BCL11A-expressing mDA neurons and their cell fate, a conditional knock-out mouse model for BCL11A in mDA neurons was generated. A set of behavioural experiments was carried out to assess whether the loss of BCL11A leads to functional impairment in the mDA system, Moreover, to elucidate the role of BCL11A expression in the context of neuronal challenges and neurodegenerative processes affecting mDA neurons in the SN, mDA neurons were challenged with a-synuclein overexpression.
The results of this study reveal that BCL11A is expressed in about a third of mDA neurons in the SN, VTA and RRF and that BCL11A-expressing mDA neurons contribute to several known subpopulations of mDA neurons. Intersectional labelling and tracing experiments show that BCL11A-expressing mDA neurons, despite their broad anatomical distribution, form a highly specific subcircuit within the DA system. BCL11A specific inactivation in mDA neurons led to changes in the anatomical positioning of BCL11A-expressing mDA neurons. Moreover, mice lacking BCL11A expression in mDA neurons show deficiencies in motor learning, suggesting that loss of BCL11A results in a functional impairment of mDA neurons. Furthermore, by challenging mDA neurons with a-synuclein overexpression, a model of Parkinson’s disease, BCL11A-expressing SN neurons have been shown to be particularly vulnerable to neurodegeneration. Additionally, the loss of BCL11A in this population increases their susceptibility to a-synuclein-induced degeneration.
This study links the developmental origin of a specific subset of mDA neurons to their vulnerability phenotype and functional and circuit specialization. Thus, the results of this study demonstrate that a better understanding of the genetically defined developmental history of mDA neurons is instrumental to understand the functional organization of the DA system and its susceptibility to neurodegeneration in the adult brain.},
url = {https://hdl.handle.net/20.500.11811/9670}
}
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