A cGMP signaling cascade controlling axonal branching and neuronal circuitry

Project Leader: Fritz Rathjen e-mail

 

Axonal branching is essential for neurons to establish contacts with different target neurons. It allows an individual neuron to communicate with others in different regions of the nervous system, thereby contributing to the generation of the structural framework of the nervous system that allows the integration and distribution of information. Within the collaborative research center, we have studied the branching of axons that project from dorsal root ganglia (DRG) into the spinal cord. We identified a cGMP signaling cascade composed of the ligand CNP (type C natriuretic peptide), the receptor guanylyl cyclase Npr2 and the cGMP-dependent kinase I (cGKI) that regulates axon bifurcation. In the absence of any of these components, DRG axons no longer bifurcate and instead turn either in a rostral or a caudal direction upon entering the spinal cord.

In the past funding period, we showed that in addition to DRG neurons, also neurons of cranial sensory ganglia (gV, gVII, gVIII, gIX and gX) express both Npr2 and cGKI at the time when their axons reach the entry zones of the hindbrain, where CNP is expressed in a complementary fashion. Using transgenic labeling of individual neurons, we demonstrated that the absence of Npr2 causes a complete loss of bifurcation of cranial sensory axons, which instead establish only either ascending or descending projections. Thus, axonal branching of cranial and dorsal root ganglia is regulated in an analogous manner by this cGMP signaling cascade.

We propose here to study the physiological deficits caused by the lack of bifurcation of sensory axons using genetic mouse models, and link such deficits to human disease. Furthermore, we plan to extend the analysis of the Npr2-dependent cGMP signaling cascade and to study possible cross talk with other intracellular signaling systems. In particular, we wish to analyze the regulation of Npr2 activity by phosphorylation/dephosphorylation of its kinase homology domain. The genetic tools established in the past will now be used to identify neuronal populations in the central nervous system whose arborization patterns are regulated by Npr2 mediated cGMP signaling.