title: Functional significance of isoform diversification in the protocadherin gamma gene cluster.
abstract: The mammalian Protocadherin (Pcdh) alpha, beta, and gamma gene clusters encode a large family of cadherin-like transmembrane proteins that are differentially expressed in individual neurons. The 22 isoforms of the Pcdhg gene cluster are diversified into A-, B-, and C-types, and the C-type isoforms differ from all other clustered Pcdhs in sequence and expression. Here, we show that mice lacking the three C-type isoforms are phenotypically indistinguishable from the Pcdhg null mutants, displaying virtually identical cellular and synaptic alterations resulting from neuronal apoptosis. By contrast, mice lacking three A-type isoforms exhibit no detectable phenotypes. Remarkably, however, genetically blocking apoptosis rescues the neonatal lethality of the C-type isoform knockouts, but not that of the Pcdhg null mutants. We conclude that the role of the Pcdhg gene cluster in neuronal survival is primarily, if not specifically, mediated by its C-type isoforms, whereas a separate role essential for postnatal development, likely in neuronal wiring, requires isoform diversity.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, 701 W. 168 Street, New York, NY 10032, USA.
authors.forename: Weisheng V
authors.initials: WV
authors.lastname: Chen
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Alvarez
authors.forename: Julie L
authors.initials: JL
authors.lastname: Lefebvre
authors.forename: Brad
authors.initials: B
authors.lastname: Friedman
authors.forename: Chiamaka
authors.initials: C
authors.lastname: Nwakeze
authors.forename: Eric
authors.initials: E
authors.lastname: Geiman
authors.forename: Courtney
authors.initials: C
authors.lastname: Smith
authors.forename: Chan Aye
authors.initials: CA
authors.lastname: Thu
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Tapia
authors.forename: Bosiljka
authors.initials: B
authors.lastname: Tasic
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sanes
authors.forename: Tom
authors.initials: T
authors.lastname: Maniatis
mesh_terms: D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism*; D002452:Cell Count; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; C464785:Gamma-protocadherins; D020033:Protein Isoforms