Signaling pathways centered around the second messenger cGMP are organized in a modular fashion combining specific cGMP-generating guanylyl cyclases with certain cGMP-dependent proteins, like phosphodiesterases, protein kinases, or ion channels. One of these pathways -cGMP signaling triggered by binding of C-type natriuretic peptide (CNP) to its receptor guanylyl cyclase B (GC-B; also named NPR2 or NPR-B) - has been linked by genetic evidence to a remarkable variety of physiological functions including endochondral ossification involved in the formation of long bones and vertebrae, oocyte maturation, cardiac growth, gastrointestinal function, and axon bifurcation.

The most obvious effect of inactivating mutations of CNP or GC-B in mice was a severe form of dwarfism, whereas overexpression of CNP or reduced clearance of CNP evoked skeletal overgrowth. Similar defects have been observed in cGMP-dependent protein kinase (cGK) II-deficient mice or in spontaneously inactivating mutations of rats suggesting that CNP activates GC-B on chondrocytes to generate cGMP which then activates cGKII to induce endochondral ossification. In humans, homozygous mutations in the gene for GC-B (NPR2) have been reported to cause one form of human skeletal dysplasias, acromesomelic dysplasia type Maroteaux (AMDM) which is a rare autosomal recessive disorder with a prevalence of approximately 1/1.000.000. This skeletal dysplasia is characterized by an extreme short stature, misshapen bones in limbs and spine as well as body disproportions. GC-B thus plays a critical role in skeletal development.

A further function of GC-B was identified by our studies on the molecular mechanisms of axonal branching which represents a key principle for the establishment of neural connectivity. Using lacZ-reporter mouse lines for expression mapping of CNP and GC-B as well as a GC-B-CreERT2 mouse model enabling genetic labeling of individual GC-B-expressing neurons we demonstrated that the cGMP signaling pathway composed of CNP, GC-B, and cGKI? is essential for the bifurcation of central axon projections of neurons from both (1) dorsal root ganglia and (2) cranial sensory ganglia in vivo. In the absence of one of these components, sensory axons no longer bifurcate and display instead only right-angled turns in either rostral or caudal direction, whereas formation of collateral branches is not affected. Consequently, the loss of sensory axon bifurcation in mutant mice results in a reduced synaptic input onto second-order neurons in the dorsal horn of the spinal cord.