Project description

ziegler at gsf.de ziegler at gsf.de
Thu Dec 11 11:35:00 EST 1997


A Postdoctoral Position

is available to work on:

Genetics, Development and Function of Pteridine related Enzymes in
Neural Crest-derived cells of the Zebra fish.

The programme is part of an EU project on  "Structure and Function of
Pteridine related Enzymes".  It should characterise two genes coding
for enzymes  which are essentially involved in the function of the
neuronal system and in the formation of the pigment pattern. Both
genes are highly conserved but their structures have thus far been
more extensively studied in mammals. The development and function of
both enzymes should be studied during normal development and in
mutants.

The successful applicant will possess a PhD and have experience in
molecular biology and a strong background in analytical
biochemistry/enzymology.

The EU rules on TMR networks allow only EU citizens outside Germany to
apply. The position will be available from March 98 or later and is
funded for 3 years. Salary will be determined according to the tariff
for Public Service in Germany (BAT IIa), ranging from  ECU 45 300 to
ECU 54 000 pa.

Please submit a curriculum vitae, a research summary and the names of
three referees. Further information can be obtained from the host
laboratories at the addresses given below.

Dr. Irmgard Ziegler     Dr.Rudolf Balling
GSF-Institute of      Head, GSF-Institute of
Clinical Molecular Biology    Mammalian Genetics
Marchioninistr.25     Ingolstaedter Landstr.1
D-81377 Muenchen     D-85764 Neuherberg

Tel.: +49-89-7099-221;     Tel.: +49-89-3187-4111;
Fax: +49-89-7099-500;    Fax:  +49-89- 3187-3099;
e-mail: ziegler at gsf.de    e-mail: balling at gsf.de

*********************************************************************
Genetics, development  and function of pteridine related enzymes in
neural crest-derived cells of the Zebra fish

Research topic
Neural crest-derived neurogenic cells and pigment cells join a
biosynthetic pathway which leads from GTP to H4biopterin. This pathway
is determined by three enzymes, two of which (GTP cyclohydrolase I and
6-pyruvoyl-H4pterin synthase) are highly conserved during evolution.
The end product  H4biopterin has a marked pleiotropic function. It is
the essential cofactor for dopamine and serotonin (and thus, for
melatonin) production. Mutations in either of these two enzymes are
well defined in mammals and humans to cause neuronal defects.
H4biopterin is an essential component of NO synthase which also was
shown to occur throughout the nervous system of fish. Finally,
H4biopterin is present in all pigment cells. In some of them (e.g.
xanthophores or iridiophores) additional  enzymatic modifications of
the pteridine core structure cause accumulation of intermediates which
absorb at different wavelengths in the visible range and thus
determine the morphological pattern. Due to these multiple functions
of H4biopterin, it is to expect that mutations affecting pteridine
related enzymes, result in complex changes presumably affecting
pigmentation and the nervous system. In large-scale mutagenesis
screens 285 mutations have been isolated, affecting all aspects of
zebra fish pigmentation pattern. About the same number of mutations
affect neuronal development and result in mutated phenotypes becoming
apparent in retina, brain or in the lateral nervous system.  In
several cases, a mutation jointly affects both the neuronal and the
pigment system. In no case the gene for these phenotypically described
mutations is located and no protein product is structurally or
functionally characterized,  so far.

Project objectives
The overall objective of this programme is to characterise the two
pteridine related enzymes GTP cyclohydrolase I and 6-pyruvoyl-H4pterin
synthase involved in the function of the neuronal system and in the
formation of the pigment pattern, and to study expression and activity
of these enzymes during normal development and the devolopment of
relevant mutants. (i) The loci of GTP cyclohydrolase I and
6-pyruvoyl-H4pterin synthase will be mapped in the Zebra fish. (ii)
Antibodies specific for GTP cyclohydrolase I and 6-pyruvoyl-H4pterin
synthase of  the Zebra fish will be produced. By this means the
expression pattern of the biopterin synthesizing system during
development of the neural crest and of neural crest-derived cells will
be analysed. It will allow to follow, e.g. the formation and
patterning of dopaminergic and serotonergic neurons, the formation of
the eye bulb and the the retinal pigment epithelium. The migration of
biopterin synthesizing cells before onset of visible pigmentation will
be followed and factors in the the surrounding tissue affecting the
expression of  both biopterin synthesizing enzymes will be analysed.
(iii) The project shall include a search for mutations in GTP
cyclohydrolase I and 6-pyruvoyl-H4pterin synthase among the mutants
generated in Tuebingen/Boston and shall analyze how such mutations
affect the developoment of pigmentation and neuronal functions. Strong
candidate mutations are those with phenotypes jointly affecting
pigment synthesis, neuronal defects by impaired neurotransmitter
synthesis, and neuronal defects by impaired NO synthesis as well.






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