NRP1 and NRP2 cooperate to regulate gangliogenesis, axon guidance and target innervation in the sympathetic nervous system

Abstract

The sympathetic nervous system (SNS) arises from neural crest (NC) cells during embryonic development and innervates the internal organs of vertebrates to modulate their stress response. NRP1 and NRP2 are receptors for guidance cues of the class 3 semaphorin (SEMA) family and are expressed in partially overlapping patterns in sympathetic NC cells and their progeny. By comparing the phenotypes of mice lacking NRP1 or its ligand SEMA3A with mice lacking NRP1 in the sympathetic versus vascular endothelial cell lineages, we demonstrate that SEMA3A signalling through NRP1 has multiple cell-autonomous roles in SNS development. These roles include neuronal cell body positioning, neuronal aggregation and axon guidance, first during sympathetic chain assembly and then to regulate the innervation of the heart and aorta. Loss of NRP2 or its ligand SEMA3F impaired sympathetic gangliogenesis more mildly than loss of SEMA3A/NRP1 signalling, but caused ectopic neurite extension along the embryonic aorta. The analysis of compound mutants lacking SEMA3A and SEMA3F or NRP1 and NRP2 in the SNS demonstrated that both signalling pathways cooperate to organise the SNS. We further show that abnormal sympathetic development in mice lacking NRP1 in the sympathetic lineage has functional consequences, as it causes sinus bradycardia, similar to mice lacking SEMA3A.

Neural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation

“…Because a role for NRP1 in cardiac NCC migration had previously been reported in chick (14), we investigated whether cardiac NCC-derived NRP1 is required for OFT septation in mice by comparing immunolabeled serial sections through the E12.5 OFTs of Wnt1-Cre Nrp1 fl/fl mutants and controls. Efficient targeting of NRP1 in the NCC lineage was previously demonstrated by similar defects in the NCC-derived sympathetic nervous systems of Wnt1-Cre Nrp1 fl/fl mutants and full Nrp1 knockouts (20). However, and in contrast with Nrp1 -/-mice, the OFTs of Wnt1-Cre Nrp1 fl/fl mutants were septated normally ( Figure 3B, top panels).…”

Netrin-1 controls sympathetic arterial innervation

“…Netrin-1 was not expressed in the heart, and cardiac innervation was normal in Ntn1 mutants. Interestingly, a growing body of evidence indicates that innervation of the heart and large arteries is regulated by other molecules, including NGF and the axon guidance molecule Sema3A and its receptor Nrp1 (41)(42)(43). Therefore, sympathetic innervation of cardiovascular targets may be regulated by specific combinations of guidance molecules: Sema3A/Nrp1 for the heart and large arteries and netrin/DCC for resistance arteries.…”

Semaphorins in cardiovascular medicine

“…These defects result in sinus bradycardia. Interestingly, a similar phenotype is observed in mice lacking Nrp1 in NCCs [35]. The overexpression of Sema3A in the adult myocardium reduces the number of sympathetic fibers and increases susceptibility to the arrhythmogenic effect of catecholamines, indicating that SEMA3A is relevant for sympathetic functions, not only during development, but also after birth [34].…”