Axon bifurcation - a specific form of branching of somatosensory axons characterized by the splitting of the growth cone - is mediated by a cGMP-dependent signaling cascade composed of the extracellular ligand CNP (C-type natriuretic peptide), the transmembrane receptor guanylyl cyclase Npr2 (natriuretic peptide receptor 2), and the kinase cGKI (cGMP-dependent protein kinase I). In the absence of any one of these components, the formation of T-shaped axonal branches is impaired in neurons from DRGs (dorsal root ganglia), CSGs (cranial sensory ganglia) and MTNs (mesencephalic trigeminal neurons) in the murine spinal cord or hindbrain. Instead, axons from DRGs or from CSGs extend only either in an ascending or descending direction, while axons from MTNs either elongate within the hindbrain or extend via the trigeminal ganglion to the masseter muscles. Collateral formation from non-bifurcating stem axons is not affected by impaired cGMP signaling. Activation of Npr2 requires both binding of the ligand CNP as well as phosphorylation of serine and threonine residues at the juxtamembrane regions of the receptor. The absence of bifurcation results in an altered shape of termination fields of sensory afferents in the spinal cord and resulted in impaired noxious heat sensation and nociception whereas motor coordination appeared normal.
Keywords: axon bifurcation; axon branching; cGMP signaling; neuronal circuit formation; somatosensory axons.