Reduced ability of C-type natriuretic peptide (CNP) to activate natriuretic peptide receptor B (NPR-B) causes dwarfism in lbab−/− mice

Yoder, Andrea R.; Kruse, Andrew C.; Earhart, C.A.; Ohlendorf, D.H.; Potter, Lincoln R.

doi:10.1016/j.peptides.2008.04.020

Cited by 18 publications

(14 citation statements)

References 33 publications

(33 reference statements)

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“…Identical errors were observed in the lbab (long bone abnormality) mouse ( Fig. 2 F and H), which contains a single point mutation in the CNP gene, resulting in an exchange of an arginine that is critical for the binding of CNP to an acidic pocket in the Npr2 receptor (26)(27)(28). Consistent with the results of the DiI tracings at embryonic stages, a bifurcation failure is also found at mature stages for all sensory axons as revealed by analyzing crosses of Thy1-YFP-H (29) reporter mice with CNPdeficient mice (Fig.…”

Section: Expression Of Cnp In the Dorsal Spinal Cord During The Ingromentioning

confidence: 64%

C-type natriuretic peptide (CNP) is a bifurcation factor for sensory neurons

Schmidt

Stonkute

Jüttner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal circuits are shaped during development by the coordinated action of guidance factors and signals that regulate axonal branching. Unlike guidance cues, the molecules and signaling cascades that underlie axonal branching remain to be resolved. Here we show that the secreted molecule C-type natriuretic peptide (CNP) induces a cGMP signaling cascade via its receptor particulate guanylyl cyclase Npr2 which is essential for sensory axon bifurcation at the dorsal root entry zone (DREZ) of the spinal cord. In contrast, another form of sensory axon branchingcollateral formation-is not affected by this pathway. We also demonstrate that cGMP signaling via the nitric oxide-stimulated soluble guanylyl cyclase system (NO-GC) is dispensable for sensory axon branching. Functionally, the bifurcation error in CNP mutant mice is maintained at mature stages and results in a reduced input on secondary neurons as detected by patch-clamp recordings.axon branching and pathfinding ͉ cGKI ͉ cGMP signaling ͉ Npr2 T he processes of growth cone guidance and axonal branching are key mechanisms in the formation of axonal pathways during the period of axonal outgrowth resulting in the complex wiring pattern of the mature nervous system (1). Branching enables an individual neuron to innervate several distinct targets providing the physical basis for the distribution and integration of information. Different modes of axon branch formation may be distinguished including: 1) ramifications that are a result of the activity of the growth cone (growth cone splitting and delayed branching) and that could lead to a bifurcation as well as complex terminal arbors and 2) generation of collateral branches at the axon shaft by budding (also termed interstitial branching) (2). The latter appears to be the dominating branching mode of projecting cortical and thalamocortical axons (3, 4).Axonal guidance factors such as Semaphorin 3A and Slit2 but also neurotrophins, growth factors, morphogens, focal adhesion kinase (FAK), and adhesion proteins have been shown to be implicated in branching in vitro (5-11). Furthermore, neuronal activity via calcium influx (12-15) as well as cytoskeletal proteins that affect axon stability influence branch formation (16)(17)(18)(19).Despite this progress, the intracellular signaling cascades that underlie both modes of axonal branching in vivo have remained poorly understood. We have therefore studied arborisation of sensory axons projecting into the spinal cord where both modes of branching can be visualized. As sensory axons enter the developing spinal cord at the dorsal root entry zone (DREZ), they split into a rostral and caudal arm. They grow over several segments but remain confined to lateral regions of the cord (20). Collaterals that grow into the gray matter are then generated after a waiting period by budding from these stem axons. Nociceptive collaterals are confined to the dorsal horn while proprioceptive collaterals terminate in the ventral cord.In our previous investigations we demonstrated that in the abs...

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Section: Expression Of Cnp In the Dorsal Spinal Cord During The Ingromentioning

confidence: 64%

C-type natriuretic peptide (CNP) is a bifurcation factor for sensory neurons

Schmidt

Stonkute

Jüttner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies have elucidated that the impaired growth of lbab/lbab mice is caused by a hypomorphic mutation in the CNP gene; Jiao et al [11] found that its impaired growth phenotype is associated with a single point mutation in the mouse CNP gene, and we showed that this phenotype is completely recovered by CNP overexpression [12]. Yoder et al [13] characterized the mutant CNP in lbab/lbab mice and demonstrated that it is less biologically active than authentic CNP; in whole-cell cGMP elevation and membrane guanylyl cyclase assays, 30-fold to greater than 100-fold more mutant CNP is required to activate GC-B compared to authentic CNP. We also confirmed that the mutant CNP in lbab/lbab mice retains only about 10% activity to induce cyclic GMP production through GC-B compared to authentic CNP in an in vitro transfection assay using COS-7 cells [12].…”

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confidence: 55%

Skeletal Analysis of the Long Bone Abnormality (lbab/lbab) Mouse, A Novel Chondrodysplastic C-Type Natriuretic Peptide Mutant

et al. 2012

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Long bone abnormality (lbab/lbab) is a strain of dwarf mice. Recent studies revealed that the phenotype is caused by a spontaneous mutation in the Nppc gene, which encodes mouse C-type natriuretic peptide (CNP). In this study, we analyzed the chondrodysplastic skeletal phenotype of lbab/lbab mice. At birth, lbab/lbab mice are only slightly shorter than their wild-type littermates. Nevertheless, lbab/lbab mice do not undergo a growth spurt, and their final body and bone lengths are only ~60% of those of wild-type mice. Histological analysis revealed that the growth plate in lbab/lbab mice, especially the hypertrophic chondrocyte layer, was significantly thinner than in wild-type mice. Overexpression of CNP in the cartilage of lbab/lbab mice restored their thinned growth plate, followed by the complete rescue of their impaired endochondral bone growth. Furthermore, the bone volume in lbab/lbab mouse was severely decreased and was recovered by CNP overexpression. On the other hand, the thickness of the growth plate of lbab/+ mice was not different from that of wild-type mice; accordingly, impaired endochondral bone growth was not observed in lbab/+ mice. In organ culture experiments, tibial explants from fetal lbab/lbab mice were significantly shorter than those from lbab/+ mice and elongated by addition of 10(-7) M CNP to the same extent as lbab/+ tibiae treated with the same dose of CNP. These results demonstrate that lbab/lbab is a novel mouse model of chondrodysplasia caused by insufficient CNP action on endochondral ossification.

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“…ANP binds GC-A at a stoichiometry of 1:2 and induces a rotation of the juxtamembrane region (3,4). Structural modeling studies suggest that CNP binds GC-B similarly (5,6). Natriuretic peptide binding is hypothesized to activate the receptors by relieving basal repression exerted by the kinase homology domains on the guanylyl cyclase domains (7,8).…”

Section: Natriuretic Peptides and Atp Activate And Gö6976 Inhibits Gumentioning

confidence: 99%

ATP Potentiates Competitive Inhibition of Guanylyl Cyclase A and B by the Staurosporine Analog, Gö6976

Robinson

Potter

2011

Journal of Biological Chemistry

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Natriuretic peptides and ATP activate and Gö6976 inhibits guanylyl cyclase (GC)-A and GC-B. Here, the mechanism of inhibition was determined. Gö6976 progressively increased the Michaelis-Menten constant and decreased the Hill coefficient without reducing the maximal velocity of GC-A and GC-B. In the presence of 1 mM ATP, the K i was 1 M for both enzymes. Inhibition of GC-B was minimal in the absence of ATP, and 1 mM ATP increased the inhibition 4-fold. In a reciprocal manner, 10 M Gö6976 increased the potency of ATP for GC-B 4-fold. In contrast to a recent study (Duda, T., Yadav, P., and Sharma, R. K. (2010) FEBS J. 277, 2550 -2553), neither staurosporine nor Gö6976 activated GC-A or GC-B. This is the first study to show that Gö6976 reduces GTP binding and the first demonstration of a competitive inhibitor of a receptor guanylyl cyclase. We conclude that Gö6976 reduces GTP binding to the catalytic site of GC-A and GC-B and that ATP increases the magnitude of the inhibition.

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Reduced ability of C-type natriuretic peptide (CNP) to activate natriuretic peptide receptor B (NPR-B) causes dwarfism in lbab−/− mice

Cited by 18 publications

References 33 publications

C-type natriuretic peptide (CNP) is a bifurcation factor for sensory neurons

C-type natriuretic peptide (CNP) is a bifurcation factor for sensory neurons

Skeletal Analysis of the Long Bone Abnormality (lbab/lbab) Mouse, A Novel Chondrodysplastic C-Type Natriuretic Peptide Mutant

ATP Potentiates Competitive Inhibition of Guanylyl Cyclase A and B by the Staurosporine Analog, Gö6976

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