title: Dorsal root ganglion axon bifurcation tolerates increased cyclic GMP levels: the role of phosphodiesterase 2A and scavenger receptor Npr3.
abstract: A cyclic GMP (cGMP) signaling pathway, comprising C-type natriuretic peptide (CNP), its guanylate cyclase receptor Npr2, and cGMP-dependent protein kinase I, is critical for the bifurcation of dorsal root ganglion (DRG) and cranial sensory ganglion axons when entering the mouse spinal cord and the hindbrain respectively. However, the identity and functional relevance of phosphodiesterases (PDEs) that degrade cGMP in DRG neurons are not completely understood. Here, we asked whether regulation of the intracellular cGMP concentration by PDEs modulates the branching of sensory axons. Real-time imaging of cGMP with a genetically encoded fluorescent cGMP sensor, RT-PCR screens, in situ hybridization, and immunohistology combined with the analysis of mutant mice identified PDE2A as the major enzyme for the degradation of CNP-induced cGMP in embryonic DRG neurons. Tracking of PDE2A-deficient DRG sensory axons in conjunction with cGMP measurements indicated that axon bifurcation tolerates increased cGMP concentrations. As we found that the natriuretic peptide scavenger receptor Npr3 is expressed by cells associated with dorsal roots but not in DRG neurons itself at early developmental stages, we analyzed axonal branching in the absence of Npr3. In Npr3-deficient mice, the majority of sensory axons showed normal bifurcation, but a small population of axons (13%) was unable to form T-like branches and generated turns in rostral or caudal directions only. Taken together, this study shows that sensory axon bifurcation is insensitive to increases of CNP-induced cGMP levels and Npr3 does not have an important scavenging function in this axonal system.
authors.affiliation: Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft, 13092, Berlin, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: Interfakultäres Institut für Biochemie, University of Tübingen, 72076, Tübingen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Peters
authors.affiliation: Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft, 13092, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Frank
authors.affiliation: Interfakultäres Institut für Biochemie, University of Tübingen, 72076, Tübingen, Germany.
authors.forename: Lai
authors.initials: L
authors.lastname: Wen
authors.affiliation: Interfakultäres Institut für Biochemie, University of Tübingen, 72076, Tübingen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.affiliation: Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft, 13092, Berlin, Germany.
authors.forename: Fritz G
authors.initials: FG
authors.lastname: Rathjen
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology*; D006152:Cyclic GMP / Q000378:metabolism*; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000378:metabolism*; D005260:Female; D005727:Ganglia, Spinal / Q000196:embryology* / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020098:Natriuretic Peptide, C-Type / Q000008:administration & dosage / Q000378:metabolism*; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020098:Natriuretic Peptide, C-Type; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C; D006152:Cyclic GMP
keywords: C-type natriuretic peptide; Npr2; Npr3; axon branching; cyclic GMP; dorsal root ganglion neurons