Abstract
The clustered protocadherin (Pcdh) genes are divided into the Pcdhα, Pcdhβ, and Pcdhγ clusters. Gene-disruption analyses in mice have revealed the in vivo functions of the Pcdhα and Pcdhγ clusters. However, all Pcdh protein isoforms form combinatorial cis-hetero dimers and enter trans-homophilic interactions. Here we addressed distinct and cooperative functions in the Pcdh clusters by generating six cluster-deletion mutants (Δα, Δβ, Δγ, Δαβ, Δβγ, and Δαβγ) and comparing their phenotypes: Δα, Δβ, and Δαβ mutants were viable and fertile; Δγ mutants lived less than 12 h; and Δβγ and Δαβγ mutants died shortly after birth. The Pcdhα, Pcdhβ, and Pcdhγ clusters were individually and cooperatively important in olfactory-axon targeting and spinal-cord neuron survival. Neurodegeneration was most severe in Δαβγ mutants, indicating that Pcdhα and Pcdhβ function cooperatively for neuronal survival. The Pcdhα, Pcdhβ, and Pcdhγ clusters share roles in olfactory-axon targeting and neuronal survival, although to different degrees.
Highlights
The clustered protocadherins (Pcdhs) are diverse cadherin-related receptors and constitute gene clusters in mammals (Kohmura et al, 1998; Wu and Maniatis, 1999)
We found that the glomerular structure appeared abnormal in single ∆α mutants, and in single ∆β and ∆γ mutants, and that the disruption of olfactory-axon projection patterns appeared more extensive in the ∆αβ and ∆βγ double-deletion and ∆αβγ triple-deletion mutants than in the single-deletion mutants (∆α, ∆β, and ∆γ ) (Figure 5A, WVL)
The severity of the neuron-loss phenotype was strongly correlated with the number of Pcdh-cluster deletions. These results showed that the Pcdhα and Pcdhβ clusters were functionally cooperative with the Pcdhγ cluster for neuronal survival in the brainstem
Summary
The clustered protocadherins (Pcdhs) are diverse cadherin-related receptors and constitute gene clusters in mammals (Kohmura et al, 1998; Wu and Maniatis, 1999). The Pcdh genes are expressed in the central and peripheral nervous systems, and their combinatorial and differential expression in individual neurons generates neuronal identity based on tremendous cell-surface diversity (Zipursky and Sanes, 2010; Weiner and Jontes, 2013; Yagi, 2014). Mammals have over 50 genes located in the Pcdhα, Pcdhβ, and Pcdhγ gene clusters, which are all on the same chromosome. All Pcdhα or Pcdhγ proteins have a common cytoplasmic tail; this does not in occur in the Pcdhβ cluster. Both the Pcdhα and Distinct and Cooperative Pcdhs Functions
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