DARWIN Digitale Dissertationen German Version Strich

FU Berlin
Digitale Dissertation

Henning Brohmann :
Lbx1 in mouse development
control of muscle precursor cell migration and neuronal specification in the spinal cord
Lbx1 in der Mausentwicklung

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Abstract

The homeodomain transcription factor Lbx1 is exclusively expressed in migrating myogenic precursor cells and in the dorsal spinal cord during embryonic development. In order to determine the function of Lbx1 in myogenesis and spinal cord development, the Lbx1 gene was inactivated in the mouse by gene targeting. Genomic Lbx1 sequences were isolated and used to construct a targeting vector. This construct allowed the mutation of Lbx1 by homologous recombination in embryonic stem cells and the establishment of a Lbx1 mutant mouse strain. Heterozygous Lbx1 mice displayed no overt phenotype, whereas homozygous Lbx1 mutants died shortly after birth and showed an abnormal limb musculature. Further analysis demonstrated, that muscle precursor cells were formed in Lbx1 mutants, but migrated aberrantly and were unable to respond or interpret guidance cues that direct them towards their target sites.
The expression of Lbx1, Pax3 and c-Met overlap in muscle progenitor cells. Analysis of the corresponding mutant mice revealed that Pax3 controls formation and specification of these cells and functions on top of a genetic hierarchy that controls the development of migrating myogenic precursor cells. c-Met and its ligand SF/HGF are essential for the delamination of this myogenic progenitor population from the dermomyotome. In addition, the adaptor protein Gab1 is essential for the transmission of the c-Met signal in vivo.
Lbx1 expression distinguishes two classes of postmitotic neurons in the dorsal spinal cord. The formation of class A neurons, which consist of the dI1-dI3 subtypes, is directed by dorsal instructive signals and these cells do not express Lbx1. In contrast, the Lbx1 positive class B neurons of the dI4-dI6 subtypes develop independently of instructive dorsal signals. In Lbx1 mutant mice, class B neurons change their differentiation program and adapt the identities of class A neurons. Therefore Lbx1 controls the specification of spinal cord neurons, which mature into dorsal interneurons and function as the first central relay station for somatosensory perception.

Table of Contents

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0. TITELBLATT UND INHALTSVERZEICHNIS
1. EINLEITUNG
1
1.1 Der Homöobox-Transkriptionsfaktor Lbx1
1
1.2 Die Entwicklung der Skelettmuskulatur bei Wirbeltieren
2
1.3 Die genetische Kontrolle der Entwicklung migrierender hypaxialer Muskelvorläuferzellen
4
1.4 Neuronale Organisation und Etablierung dorso-ventraler Polarität im embryonalen Rückenmark
8
1.5 Ziele der vorliegenden Arbeit
12
2. MATERIAL UND METHODEN
13
2.1 Material
13
2.2 Methoden
16
3. ERGEBNISSE
36
3.1 Analyse der Funktion von Lbx1 in der Mausentwicklung
36
3.2 Phänotypische Analyse der Lbx1-Mutation
40
3.3 Lbx1 als Komponente einer genetischen Hierarchie zur Kontrolle der Entwicklung wandernder Muskelvorläuferzellen
48
3.4 Die Funktion von Lbx1 in der Neurogenese
55
4. DISKUSSION
65
4.1 Die Funktion von Lbx1 in der Maus-Entwicklung
65
4.2 Kontrolle der Delamination migrierender Muskelvorläuferzellen durch das SF/HGF/c-Met-Signalsystem 69
4.3 Gab1 als essentielle Komponente für die Weiterleitung des c-Met-Signals 72
4.4 Die genetische Hierarchie zur Kontrolle der Entwicklung migrierender Muskelvorläuferzellen 73
4.5 Spezifizierung der Lbx1-Nervenzellen im dorsalen Neuralrohr 76
4.6 Veränderungen im Diffenzierungsprogramm dorsaler Neurone in Lbx1-Mutanten 78
5. ZUSAMMENFASSUNG - SUMMARY 81
6. LITERATURVERZEICHNIS 83

More Information:

Online available: http://www.diss.fu-berlin.de/2002/213/indexe.html
Language of PhDThesis: german
Keywords: Lbx1, muscle precursor cells, spinal cord
DNB-Sachgruppe: 32 Biologie
Date of disputation: 14-Oct-2002
PhDThesis from: Fachbereich Biologie, Chemie, Pharmazie, Freie Universität Berlin
First Referee: PD Dr. Carmen Birchmeier
Second Referee: Prof. Dr. Ferdinand Hucho
Contact (Author): brohmann@mdc-berlin.de
Date created:22-Oct-2002
Date available:23-Oct-2002

 

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