Article

cGMP signaling and bifurcation of sensory axons at the dorsal root entry zone of the spinal cord

GBG Forschungs-GmbH, Neu-Isenburg, Germany
BMC Pharmacology (Impact Factor: 1.84). 01/2007; 7:1-2. DOI: 10.1186/1471-2210-7-S1-S47
Source: DOAJ

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Available from: René Jüttner
BioMed Central
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BMC Pharmacology
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Oral presentation
cGMP signaling and bifurcation of sensory axons at the dorsal root
entry zone of the spinal cord
Agne Stonkute*
1
, Hannes Schmidt
1
, Rene Jüttner
1
, Susanne Schäffer
1,3
,
Jens Buttgereit
1
, Robert Feil
2,4
, Franz Hofmann
2
and Fritz G Rathjen
1
Address:
1
Developmental Neurobiology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany,
2
Institute for Pharmacology und
Toxicology, Technical University of München, Germany,
3
GBG Forschungs-GmbH, Neu-Isenburg, Germany and
4
Interfaculty Institute for
Biochemistry, University of Tübingen, Germany
Email: Agne Stonkute* - stonkute@mdc-berlin.de
* Corresponding author
Background
The function of the nervous system depends on precise
and selective connections of neurons. Various guidance
cues instruct axons in choosing their pathway, polarity of
growth, termination of growth and also branching. In
vitro studies demonstrated that signaling cascades acti-
vated by axonal guidance receptors could be modulated
by cyclic nucleotides. Previous analyses of cGKI (cGMP
dependent protein kinase I) deficient mice in our lab
showed that cGMP signaling via cGKI is important in
axonal pathfinding and connectivity of sensory neurons.
Sensory axons bifurcate upon arrival at the dorsal root
entry zone (DREZ) of the spinal cord. Embryonic cGKI
knock-out mice lack the bifurcation of sensory axons at
the DREZ, i.e. the ingrowing axon either turns rostrally or
caudally. Here, we present results of the detailed analysis
of axonal pathfinding errors in cGKI deficient mice and of
the search for other components of cGMP signaling in
dorsal root ganglions (DRG).
Results
DiI tracing studies carried out before, were limited to the
visualization of bundles of axons, which did not allow to
quantify errors of single axons. Therefore, we extended
our DiI tracing studies to the single axon level. Thereby,
we could confirm statistically significant deviations
(absence of T-shaped bifurcations) in the pattern of
ingrowing sensory axons of cGKI knock-out mice as com-
pared to the wild-type.
Screens for a role of guanylyl cyclases in sensory axon
bifurcation carried out in our lab suggest that the natriu-
retic peptide receptor 2 (Npr2) might serve such a func-
tion in DRG neurons. We studied embryos of mice lacking
functional Npr2 using DiI labelling and observed axonal
bifurcation errors identical to that in cGKI knock-out
mice.
Cross-breeding experiments with the transgenic mouse
line GFP-M expressing GFP in a small proportion of DRG
neurons provide further evidence for the bifurcation
errors in cGKI deficient mice and Npr2 mutant mice. The
resulting offspring was analyzed at postnatal day 21 indi-
cating that bifurcation errors remain in adult animals.
Interestingly, whereas sensory axons in the spinal cord of
cGKI mutant animals do not bifurcate other types of sen-
sory axon branching seem not to be affected: we could
detect collaterals formed by interstitial branching from
the longitudinal arms of sensory axons both in wild-type
and mutant mice.
We show that the vasodilator-stimulated phosphoprotein
(VASP) is phosphorylated in dorsal root ganglions upon
from 3
rd
International Conference on cGMP Generators, Effectors and Therapeutic Implications
Dresden, Germany. 15–17 June 2007
Published: 25 July 2007
BMC Pharmacology 2007, 7(Suppl 1):S47 doi:10.1186/1471-2210-7-S1-S47
<supplement> <title> <p>3<sup>rd </sup>International Conference on cGMP Generators, Effectors and Therapeutic Implications</p> </title> <note>Meeting abstracts – A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1471-2210-7-S1-full.pdf">here</a>.</note> </supplement>
This abstract is available from: http://www.biomedcentral.com/1471-2210/7/S1/S47
© 2007 Stonkute et al; licensee BioMed Central Ltd.
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stimulation of cGKI. Since VASP has a role in cytoskeletal
organisation we considered that VASP might be a down-
stream target of cGKI involved in axonal pathfinding.
However, the examination of VASP knock-out mice
revealed no pathfinding errors of sensory axons.
Conclusion
We could show that cGMP acting via cGKI triggers bifur-
cation of sensory axons at the DREZ of the spinal cord.
The absence of functional Npr2 results in a phenotype
identical to that observed in cGKI knock-out mice suggest-
ing that both Npr2 and cGKI are part of a cGMP signaling
pathway important for sensory axon bifurcation. Cur-
rently, we aim to extend our insight into the mechanism
of sensory axon bifurcation by identification of down-
stream target(s) of cGKI in sensory axons.
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