Isoform requirement of clustered protocadherin for preventing neuronal apoptosis and neonatal lethality
Hiroaki Kobayashi,
Kenji Takemoto,
Makoto Sanbo,
Masumi Hirabayashi,
Takahiro Hirabayashi,
Teruyoshi Hirayama,
Hiroshi Kiyonari,
Takaya Abe,
Takeshi Yagi
Affiliations
Hiroaki Kobayashi
KOKORO-Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan; Division of Biophysical Engineering, Department of Systems Science, School of Engineering Science, Osaka University, Toyonaka 565-8531, Japan
Kenji Takemoto
KOKORO-Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan
Makoto Sanbo
Section of Mammalian Transgenesis, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki 444-8585, Japan
Masumi Hirabayashi
Section of Mammalian Transgenesis, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki 444-8585, Japan
Takahiro Hirabayashi
KOKORO-Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan
Teruyoshi Hirayama
KOKORO-Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan; Department of Anatomy and Developmental Neurobiology, Tokushima University, Graduate School of Medical Science, Tokushima 770-8503, Japan
Hiroshi Kiyonari
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 6500047, Japan
Takaya Abe
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 6500047, Japan
Takeshi Yagi
KOKORO-Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan; Division of Biophysical Engineering, Department of Systems Science, School of Engineering Science, Osaka University, Toyonaka 565-8531, Japan; Corresponding author
Summary: Clustered protocadherin is a family of cell-surface recognition molecules implicated in neuronal connectivity that has a diverse isoform repertoire and homophilic binding specificity. Mice have 58 isoforms, encoded by Pcdhα, β, and γ gene clusters, and mutant mice lacking all isoforms died after birth, displaying massive neuronal apoptosis and synapse loss. The current hypothesis is that the three specific γC-type isoforms, especially γC4, are essential for the phenotype, raising the question about the necessity of isoform diversity. We generated TC mutant mice that expressed the three γC-type isoforms but lacked all the other 55 isoforms. The TC mutants died immediately after birth, showing massive neuronal death, and γC3 or γC4 expression did not prevent apoptosis. Restoring the α- and β-clusters with the three γC alleles rescued the phenotype, suggesting that along with the three γC-type isoforms, other isoforms are also required for the survival of neurons and individual mice.
