The protocadherin-α family is involved in axonal coalescence of olfactory sensory neurons into glomeruli of the olfactory bulb in mouse

Hasegawa, Sonoko; Hamada, Shin; Kumode, You; Esumi, Shigeyuki; Katori, Shota; Fukuda, Emi; Uchiyama, Yasuo; Hirabayashi, Takahiro; Mombaerts, Peter; Yagi, Takeshi

doi:10.1016/j.mcn.2008.01.016

Cited by 126 publications

(168 citation statements)

References 72 publications

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“…Production of Mice Carrying the G1loxP Allele-The G1loxP mice, in which a loxP site was inserted into the genomic region 3-kb upstream from the CR1 exon, were described previously (14).…”

Section: Methodsmentioning

confidence: 99%

“…1, B-D). First, the "G1loxP" allele (14) was generated by inserting a loxP site between the ac2 exon and the first exon of the constant region (CR1) in the Pcdha cluster (Fig. 1B).…”

Section: Deletions and Duplications Of The Pcdhamentioning

confidence: 99%

“…The clustered Pcdh-␣ (Pcdha), Pcdh-␤, and Pcdh-␥ family genes encode cadherinrelated transmembrane proteins (4, 8 -10). 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).…”

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confidence: 99%

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

Noguchi

Hirabayashi

Katori

et al. 2009

Journal of Biological Chemistry

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The clustered protocadherin-␣ (Pcdha) genes, which are expressed in the vertebrate brain, encode diverse membrane proteins whose functions are involved in axonal projection and in learning and memory. The Pcdha cluster consists of 14 tandemly arranged genes (Pcdha1-Pcdha12, Pcdhac1, and Pcdhac2, from 5 to 3). Each first exon (the variable exons) is transcribed from its own promoter, and spliced to the constant exons, which are common to all the Pcdha genes. Cerebellar Purkinje cells show dual expression patterns for Pcdha. In individual Purkinje cells, different sets of the 5 genes in the cluster, Pcdha1-12, are randomly expressed, whereas both 3 genes, Pcdhac1 and Pcdhac2, are expressed constitutively. To elucidate the relationship between the genomic structure of the Pcdha cluster and their expression in Purkinje cells, we deleted or duplicated multiple variable exons and analyzed the expression of Pcdha genes in the mouse brain. In all mutant mice, transcript levels of the constant exons and the dual expression patterns were maintained. In the deletion mutants, the missing genes were flexibly compensated by the remaining variable exons. On the other hand, in duplication mutants, the levels of the duplicated genes were trimmed. These results indicate that the Pcdha genes are comprehensively regulated as a cluster unit, and that the regulators that randomly and constitutively drive Pcdha gene expression are intact in the deleted or duplicated mutant alleles. These dual regulatory mechanisms may play important roles in the diversity and fundamental functions of neurons.

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“…Production of Mice Carrying the G1loxP Allele-The G1loxP mice, in which a loxP site was inserted into the genomic region 3-kb upstream from the CR1 exon, were described previously (14).…”

Section: Methodsmentioning

confidence: 99%

“…1, B-D). First, the "G1loxP" allele (14) was generated by inserting a loxP site between the ac2 exon and the first exon of the constant region (CR1) in the Pcdha cluster (Fig. 1B).…”

Section: Deletions and Duplications Of The Pcdhamentioning

confidence: 99%

mentioning

confidence: 99%

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

Noguchi

Hirabayashi

Katori

et al. 2009

Journal of Biological Chemistry

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“…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).…”

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confidence: 99%

Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

Schalm

Ballif

Buchanan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The clustered protocadherins (Pcdhs) are a large family of cadherinlike transmembrane proteins expressed in the nervous system. Stochastic expression of Pcdh genes and alternative splicing of their pre-mRNAs have the potential to generate enormous protein diversity at the cell surface of neurons. At present, the regulation and function of Pcdh proteins are largely unknown. Here, we show that Pcdhs form a heteromeric signaling complex(es), consisting of multiple Pcdh isoforms, receptor tyrosine kinases, phosphatases, and cell adhesion molecules. In particular, we find that the receptor tyrosine kinase rearranged during transformation (Ret) binds to Pcdhs in differentiated neuroblastoma cells and is required for stabilization and differentiation-induced phosphorylation of Pcdh proteins. In addition, the Ret ligand glial cell line-derived neurotrophic factor induces phosphorylation of Pcdhγ in motor neurons and phosphorylation of Pcdhα and Pcdhγ in sympathetic neurons. Conversely, Pcdh proteins are also required for the stabilization of activated Ret in neuroblastoma cells and sympathetic ganglia. Thus, Pcdhs and Ret are functional components of a phosphorylationdependent signaling complex. intracellular domain | signal transduction | TAP tag | protein-protein interactions | protein purification

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“…Depending on the cellular context, mutations in the Pcdhγ gene cluster display both cell autonomous and non-cell-autonomous effects (11,14). Mutations in the Pcdhα gene cluster do not appear to affect cell viability or synapse number, but have been reported to disrupt the formation of proper glomeruli in the olfactory bulb and the innervation of target areas by serotonergic neurons (15,16). In addition, both Pcdhα and -γ have been shown to bind to each other and the tyrosine kinases PYK2, FAK (17), and Ret (18) and to a variety of other signaling molecules.…”

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confidence: 99%

Proteolytic processing of protocadherin proteins requires endocytosis

Buchanan

Schalm

Maniatis

2010

Proc. Natl. Acad. Sci. U.S.A.

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The α-, β-, and γ-protocadherins (Pcdhα, Pcdhβ, and Pcdhγ) comprise a large family of single-pass transmembrane proteins predominantly expressed in the nervous system. These proteins contain six cadherin-like extracellular domains, and proteolysis of Pcdhα and Pcdhγ by the γ-secretase complex releases their intracellular domains into the cytoplasm where they may function locally and/ or enter the nucleus and affect gene expression. Thus, cleavage of Pcdhs may function to link intercellular contacts and intracellular signaling. Here we report that shedding of the Pcdhα extracellular domain and subsequent processing by γ-secretase require endocytosis and that Pcdhs interact with the regulator of vesicular sorting ESCRT-0 in undifferentiated cells. We also find that the accumulation of Pcdh cleavage products is regulated during development. Differentiation leads to an increase in the interactions between Pcdh proteins and a decrease in the accumulation of cleavage products. We conclude that Pcdh processing requires endocytosis and that the level of cleavage products is regulated during neuronal differentiation.γ-secretase | hepatocyte growth factor-regulated tyrosine kinase substrate | neurodevelopment | protein-protein interactions | proteolysis

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The protocadherin-α family is involved in axonal coalescence of olfactory sensory neurons into glomeruli of the olfactory bulb in mouse

Cited by 126 publications

References 72 publications

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

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

Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

Proteolytic processing of protocadherin proteins requires endocytosis

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