Graduate School of Frontier Biosciences, Osaka University

Japanese

Protocadherin-α family is required for serotonergic projections to appropriately innervate target brain areas.

Journal J Neurosci 29, 9137-9147 (2009)
Authors Shota Katori, Shun Hamada, Yukiko Noguchi, Emi Fukuda, Toshifumi Yamamoto, Hideko Yamamoto, Sonoko Hasegawa and Takeshi Yagi
Title Protocadherin-α family is required for serotonergic projections to appropriately innervate target brain areas.
PubMed 19625505
Laboratory KOKORO-Biology Group 〈Prof. Yagi〉
Abstract Serotonergic axons from the raphe nuclei in the brain stem 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-alpha (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 (WT), 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 WT, and in the dentate gyrus of the hippocampus and the caudate putamen, 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.

 

Fig 1 (A) Summary of Pcdha mutant alleles and their products. Pcdha genes consist of variable region (VR) exons (1-12, c1 and c2; green) and constant region (CR) exons (CR1-CR3). The individual VR exons are transcribed from their own promoter (orange arrows). A Pcdha transcript is produced from one of the variable region exons and a set of CR exons by splicing. In the wild-type (WT) allele, the CR exons consist of a common coding region (red), and a 3' UTR (white). Pcdha proteins are single-pass membrane proteins. The extracellular, transmembrane (TM) and cytoplasmic domains are encoded in the VR exons, and their cytoplasmic domain is encoded in the CR exons. In the CR allele, the coding region of the CR exons was deleted. From the CR allele, CR-deleted Pcdha proteins (CR) were faintly expressed. (B) A Pcdha-CR probe was designed for in situ hybridization. Strong signals for Pcdha transcripts were detected in the raphe nuclei, neocortex and hippocampus. The raphe nuclei contain serotonergic neurons.



fig1.jpgのサムネール画像

Fig 2 Altered distributions of serotonergic fibers of PcdhaCR/CR mice. SERT-immunopositive fibers of WT and PcdhaCR/CR mice in horizontal sections through the hippocampus (CA) and entorhinal cortex (Ent). Serotonergic fibers innervated the molecular layer of the Ent and stratum lacunosum-moleculare of CA1 more densely in the PcdhaCR/CR mice than in WT mice. Rostral is up; lateral is to the left. DG, dentate gyrus; DLG, dorsal lateral geniculate nucleus; PaS, parasubiculum; PrS, presubiculum.


fig2.jpg

Fig 3 Altered distributions of serotonergic fibers in the thalamus of PcdhaCR/CR mice. SERT-immunopositive fibers in sagittal sections of the lateral (LG) and medial geniculate nuclei (MG) of WT and PcdhaCR/CR mice at P7 and P21. Rostral is to the left. In WT mice, the LG and MG were almost evenly innervated by serotonergic fibers whereas in the PcdhaCR/CR mice serotonergic fibers more densely concentrated around these nuclei and were sparse in the central regions of these nuclei.


fig3.jpg

Fig 4 Abnormality of serotonergic projections in the Pcdha-deficient mice. At middle stage for development, both WT and PcdhaCR/CR mice were not different for serotonergic projections. At late stage, targeted brain regions in WT mice are almost evenly innervated by serotonergic fibers, whereas in the PcdhaCR/CR mice serotonergic fibers more densely concentrate around these nuclei and are sparse in the central regions of these nuclei.


fig4.jpg