Protocadherin-α Family Is Required for Serotonergic Projections to Appropriately Innervate Target Brain Areas

Abstract

Serotonergic axons from the raphe nuclei in the brainstem project to every region of the brain, where they make connections through their extensive terminal arborizations. This serotonergic innervation contributes to various normal behaviors and psychiatric disorders. The protocadherin-␣ (Pcdha) family of clustered protocadherins consists of 14 cadherin-related molecules generated from a single gene cluster. We found that the Pcdhas were strongly expressed in the serotonergic neurons. To elucidate their roles, we examined serotonergic fibers in a mouse mutant (Pcdha ⌬CR/⌬CR ) lacking the Pcdha cytoplasmic region-encoding exons, which are common to the gene cluster. In the first week after birth, the distribution pattern of serotonergic fibers in Pcdha ⌬CR/⌬CR mice was similar to wild-type, but by 3 weeks of age, when the serotonergic axonal termini complete their arborizations, the distribution of the projections was abnormal. In some target regions, notably the globus pallidus and substantia nigra, the normally even distribution of serotonin axonal terminals was, in the mutants, dense at the periphery of each region, but sparse in the center. In the stratum lacunosum-moleculare of the hippocampus, the mutants showed denser serotonergic innervation than in wild-type, and in the dentate gyrus of the hippocampus and the caudateputamen, the innervation was sparser. Together, the abnormalities suggested that Pcdha proteins are important in the late-stage maturation of serotonergic projections. Further examination of alternatively spliced exons encoding the cytoplasmic tail showed that the A-type (but not the B-type) cytoplasmic tail was essential for the normal development of serotonergic projections.

A Genetically Defined Morphologically and Functionally Unique Subset of 5-HT Neurons in the Mouse Raphe Nuclei

“…Growth characteristics of the Pet1-resistant raphe neurons and the topography of their projections were unchanged, whereas the Pet1-dependent raphe 5-HT neurons appeared to lose not only their serotonin phenotype, but also their normal projections to the forebrain, as indicated by the lack of projections in the hippocampus (present study) and reduced projections to the somatosensory cortex (Liu et al, 2010). In this respect, the present observations in Pet1 knock-out mice differ from previous descriptions of altered distribution of 5-HT fibers, in the GAP43 or the protocadherin ␣ knock-out mice for example, which are characterized by an abnormal growth of the ascending raphe neurons (Donovan et al, 2002), or organization of 5-HT axons in target structures (Katori et al, 2009).…”

Total Expression and Dual Gene-regulatory Mechanisms Maintained in Deletions and Duplications of the Pcdha Cluster

“…In mouse, the Pcdh proteins are widely expressed in neurons (4,11,12), and localize to axons and synaptic junctions (4,(11)(12)(13)(14)(15). Their loss of function in mice revealed that the Pcdhs play important roles in neuronal survival (13), synaptic connectivity (16), axonal convergence (14), learning and memory (17), and axonal projections of serotonergic neurons (18). These results highlight the Pcdhs as candidate molecules for specifying neuronal identity in the nervous system.…”

Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

“…Pcdhα mutant mice that lack the common cytoplasmic domain show defects in the targeting of olfactory sensory neurons into glomeruli (11) and abnormal arborization of serotonergic projections (12). Deletion of the Pcdhγ gene cluster causes excessive apoptosis of interneurons in the spinal cord and retina and a decrease in synapse number of spinal cord interneurons (13)(14)(15).…”