Download Anatomie und Zellbiologie: Simon - Medizinische Fakultät Heidelberg

Arbeitsgruppe - Simon
Arbeitsgruppe - Simon
Dr. Horst Simon
Institut für Anatomie and Zellbiologie III
Universität Heidelberg
Im Neuenheimer Feld 307
69120 Heidelberg, Germany
Tel: - 49 - 6221 - 54 8342
Fax: - 49 - 6221 - 54 5605
E-Mail: [email protected]
Development of the midbrain dopaminergic neurons
PhD 1993 Guy`s Hospital, University of London, UK,
Postdoctoral work at the Salk Institute, La Jolla, USA,
Group Leader at the Department of Anatomy and Cell Biology III, IZN, since July 1999.
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Current Research
Structure of the Group
Group Leader
Horst Simon
Graduate students
Sandrine Thuret
Paola Sgadó
Murat-Burak Yaylaoglu
Daniel Gherbassi
Lavinia Alberí
Lavinia Bhatt
Undergraduate student Christian Scholz
Technicians
Gabi Döderlein
Current Research
The dopaminergic neurons (DA) of the substantia nigra and ventral tegmentum are located in the midbrain
and are the main source of dopamine in the vertebrate central nervous system. They play a major role in the
modulation of the neurons in the basal ganglia, a component of the vertebrate motor system. Parkinson?s
Disease, one of the most prominent human neurodegenerative disease, is directly linked to loss of these
neurons.
Engrailed and the midbrain dopaminergic neurons
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Engrailed and the midbrain dopaminergic neurons
Transcription factors are DNA binding elements, which
regulate the expression of other genes as activators or repressors. They play a major role in the formation and
maintenance of cellular properties during development and in the adult. En-1 and En-2 are two homeodomain
containing transcription factors which were originally cloned by sequence homology to the Drosophila
engrailed gene. One of their main expression domain is the cluster of DA neurons in the ventral midbrain. We
demonstrated recently by mouse mutant analysis that engrailed expression is essential for the proper
differentiation and maintenance of the midbrain DA neurons. The DA neurons of mice deficient of En-1 and
En-2 develop normally in the ventral midbrain and start to express molecules typical for their subclass, like
for example tyrosine hydroxylase (see image below). Soon thereafter, they disappear at developmental stage
when En-1 and En-2 are normally expressed in the wildtype. Furthermore, these studies revealed that
a-Synuclein, a membrane associated protein, which was recently genetically linked to Parkinson?s Disease, is
dependent on its expression in the DA neurons on the presence of these two transcription factors.
Downstream targets of the engrailed genes
P0 mouse brain, wildtype(right) and mutant (left) deficient of En-1 and En-2 stained against tyrosine
hydroxylase delineating the midbrain dopaminergic neurons (arrow), which are absent in the mutant.
The disappearance of the substantia nigra and ventral tegmentum in mutant mice for En-1 and En-2 suggests
that some essential downstream targets are wrongly regulated in their expression. We applied a recently
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Downstream targets of the engrailed genes
modified differential display method to identify genes which are under regulatory control of the En-1 and
En-2. Up to date, we identified several genes specifically expressed in the DA neurons and started to analyze
their function by mouse mutant studies and in cell culture.
Future Projects and Goals
The developmental cascade which leads to the proper formation of the DA neurons in the ventral midbrain are
not very well understood. Up to date, only a small amount of genes were successfully linked to their
development. Furthermore, only little is known of the proteins which Parkinson's Disease acts upon. Our main
emphasis will be the isolation, identification and functional characterization of genes, which are key players in
this developmental cascade. The differential display identified several cDNA fragments which are likely
candidate molecules. The short term aim will be to analyze these cDNA fragments and to determine their in
vivo function. This analysis will include the creation of mouse knock out animals and conditional mutants if
required or the use of cell culture systems. Long term goal will be to determine the regulatory elements which
underlies the proper initiation of the expression of these genes and how this expression is maintained during
the adult.
In situ hybridization of differentially expressed genes on P0 brain sections. Each shows a distinct expression
in the DA neurons.
Furthermore, the laboratory tries to identify the molecules involved in guiding the axons originating from the
DA neurons in the substantia nigra and ventral tegmentum to the developing basal ganglia. We will use
explant cultures in 3-D collagen matrices to identify molecules with tropic or trophic activity towards the
midbrain DA neurons. Since one of the therapeutical approaches to PD is the transplantation of embryonic
tissue containing the DA neurons, such molecules could be administered in conjunction with embryonic tissue
implants to facilitate their establishment in the basal ganglia.
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Selected Publications
Selected Publications
[1] Simon, H., and Lumsden, A. (1993). Rhombomere-specific origin of the contralateral vestibulo-acoustic
efferent neurons and their migration across the embryonic midline, Neuron 11, 209-20.
[2] Gassmann, M., Casagranda, F., Orioli, D., Simon, H., Lai, C., Klein, R., and Lemke, G. (1995). Aberrant
neural and cardiac development in mice lacking the ErbB4 neuregulin receptor, Nature 378, 390-4.
[3] Simon, H., Hornbruch, A., and Lumsden, A. (1995). Independent assignment of antero-posterior and
dorso-ventral positional values in the developing chick hindbrain, Curr Biol 5, 205-14.
[4] Yee, K. T., Simon, H. H., Tessier-Lavigne, M., and O'Leary, D. M. (1999). Extension of long leading
processes and neuronal migration in the mammalian brain directed by the chemoattractant netrin-1, Neuron
24, 607-22.
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