Details

Autor(en) / Beteiligte

• Chen, Weisheng V.
• Alvarez, Francisco J.
• Lefebvre, Julie L.
• Friedman, Brad
• Nwakeze, Chiamaka
• Geiman, Eric
• Smith, Courtney
• Thu, Chan Aye
• Tapia, Juan Carlos
• Tasic, Bosiljka
• Sanes, Joshua R.
• Maniatis, Tom

Titel

Functional Significance of Isoform Diversification in the Protocadherin Gamma Gene Cluster

Ist Teil von

• Neuron (Cambridge, Mass.), 2012-08, Vol.75 (3), p.402-409

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek

Beschreibungen/Notizen

• 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. ► Mice lacking the three C-type Pcdhg isoforms phenocopy mice lacking all 22 isoforms ► Indistinguishable cellular and synaptic changes resulting from neuronal apoptosis ► Bax deficiency rescues the lethality of C-type knockouts but not that of null mutants ► Mice lacking three A-type Pcdhg isoforms are phenotypically normal Previous studies have indicated that the protocadherin gamma gene cluster is required for neuronal survival. Here, Chen et al. show that this role appears to be specifically mediated by the C-type genes, revealing the functional divergence of protocadherin isoforms.