Uni-Tübingen

P7: CNP-induced cGMP signaling in the nervous system

Aims

To understand the role of CNP-induced cGMP signaling in the formation and maturation of neural connections in (i) dorsal root ganglion neurons and (ii) dentate granule neurons.

cGMP in sensory axon branching and hippocampal function

Questions and Methods

  • Analyze the role of candidate cGKI phosphorylation substrates in sensory axon bifurcation using biochemical assays, transgenic mouse models, and in ovo electroporated chicken DRG neurons.
  • Use FRET imaging of CNP-induced cGMP signals in a stable cell line or in chicken DRG neurons recombinantly expressing a cGMP-sensor to dissect the intracellular regulation of GC-B guanylyl cyclase activity.
  • Investigate the transcriptional effects of CNP-induced cGMP signaling in embryonic DRG neurons using transcriptomic profiling of DRG neurons from GC-B heterozygous and KO mice.
  • Use "cGi500-sensor mice" for cGMP/FRET measurements to characterize components of cGMP signaling in hippocampal neurons and study the effects of cGMP-modulating drugs (PDE- and phosphatase-inhibitors and BAY compounds).
  • Study the impact of impaired cGMP signaling on synapse and spine densities in dentate granule neurons.
  • Test the explorative behavior, spatial reference, and working memory in dentate granule cell-specific knockout mouse models of cGMP signaling components.

Boston Internship

Jacob Lab

In the Jacob lab in Boston, the doctoral researchers will be trained in the quantitative microscopic analysis of synaptic spine density and morphology for a subsequent comparison of dendritic spine properties in dentate granule cells from wild-type and GC-B KO mice.

Boston Co-mentor

Prof. Michele H Jacob, Ph.D.

Link to Boston researcher lab

Doctoral Students

Alexandra Böttcher (graduated in March 2024)

© Alexandra Böttcher

Alexandra Böttcher started her studies in the field of biochemistry at Ulm University, conducting her Bachelor's thesis on electrophysiological analysis of the dopamine response of substantia nigra neurons. Taking the opportunity to follow her interest in neurophysiological research, she continued at Ulm University and earned her Master's degree in Molecular and Translational Neuroscience. Her thesis focused on the influence of the gut microbiome on chronic psychosocial stress. Aiming to utilize innovative biochemical methodology in neuroscientific research, Alexandra joined the group of Hannes Schmidt as a doctoral student. Her main research interest lies in the role of cGMP signaling in sensory axon branching during embryonal spinal cord development.

Shahzad Munir

© Shahzad Munir

Shahzad Munir completed his bachelor in biological sciences from the Heidelberg University where he demonstrated a potential interaction between ERM protein family and membrane-bound activated leukocyte cell adhesion molecule (ALCAM) which plays a crucial role in axonal guidance and pathfinding during development. Continuing his master studies at Heidelberg University, he characterized a novel zeolite-based monoaminergic sensor, which culminated into his master thesis. His interest in fundamental neuroscience research led him to join the group of Dr. Hannes Schmidt to investigate the CNP-induced cGMP signalling in the hippocampus.

Michael Krämer (associated PhD student, graduated summer 2022)

© Michael Krämer

Michael Krämer earned his B.Sc. in biochemistry at the University of Tübingen with a focus on proteomics and protein biochemistry. After his bachelors, he went to continue with his studies in protein biochemistry and earned his M.Sc. in biochemistry also in Tübingen. Michael's keen interest in protein interactions and cellular signaling prompted him to start a PhD at the laboratory of PD Dr. Hannes Schmidt. Among other things, his main research interest focuses on CNP/GC-B mediated cGMP signaling in the gastrointestinal tract.

Key Publications

Schmidt H, Böttcher A, Gross T, Schmidtko A. cGMP signalling in dorsal root ganglia and the spinal cord: various functions in development and adulthood. Br J Pharmacol 2021, 179:361-2377.

Zalucki O, Harris L, Harvey TJ, Harkins D, Widagdo J, Oishi S, Matuzelski E, Yong XLH, Schmidt H, Anggono V, Burne THJ, Gronostajski RM, Piper M. NFIX-mediated inhibition of neuroblast branching regulates migration within the adult mouse ventricular-subventricular zone. Cereb Cortex 2019; 29: 3590.

Schmidt H, Dickey DM, Dumoulin A, Octave M, Robinson JW, Kuhn R, Feil R, Potter LR, Rathjen FG. Regulation of the natriuretic peptide receptor 2 (Npr2) by phosphorylation of juxtamembrane serine and threonine residues is essential for bifurcation of sensory axons. J Neurosci 2018, 38:9768-80.

Wolter S, Mohrle D, Schmidt H, Pfeiffer S, Zelle D, Eckert P, Kramer M, Feil R, Pilz PKD, Knipper M, Ruttiger L. GC-B deficient mice with axon bifurcation loss exhibit compromised auditory processing. Front Neural Circuits 2018; 12:65.

Subramanian H, Froese A, Jönsson P, Schmidt H, Gorelik J, Nikolaev VO Distinct submembrane localisation compartmentalises cardiac NPR1 and NPR2 signalling to cGMP. Nat Commun 2018; 9(1): 2446.

Ter-Avetisyan G, Rathjen FG, Schmidt H. Bifurcation of axons from cranial sensory neurons is disabled in the absence of Npr2-induced cGMP signaling. J Neurosci 2014, 34:737-47