2019
DOI: 10.1371/journal.pgen.1008554
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CRISPR/Cas9 interrogation of the mouse Pcdhg gene cluster reveals a crucial isoform-specific role for Pcdhgc4

Abstract: The mammalian Pcdhg gene cluster encodes a family of 22 cell adhesion molecules, the gamma-Protocadherins (γ-Pcdhs), critical for neuronal survival and neural circuit formation. The extent to which isoform diversity-a γ-Pcdh hallmark-is required for their functions remains unclear. We used a CRISPR/Cas9 approach to reduce isoform diversity, targeting each Pcdhg variable exon with pooled sgRNAs to generate an allelic series of 26 mouse lines with 1 to 21 isoforms disrupted via discrete indels at guide sites and… Show more

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Cited by 42 publications
(67 citation statements)
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References 75 publications
(137 reference statements)
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“…Overall, regulation of Pcdh cell surface expression is of central importance in several neurobiological processes, such as neuronal recognition or neural cell survival. In this context, the identity of Pcdhs involved in cell-cell interactions seems to particularly matter, as for instance PcdhγC4 was identified as a neuronal pro-survival isoform within the γ-Pcdh cluster (Garrett et al, 2019).…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…Overall, regulation of Pcdh cell surface expression is of central importance in several neurobiological processes, such as neuronal recognition or neural cell survival. In this context, the identity of Pcdhs involved in cell-cell interactions seems to particularly matter, as for instance PcdhγC4 was identified as a neuronal pro-survival isoform within the γ-Pcdh cluster (Garrett et al, 2019).…”
Section: Resultsmentioning
confidence: 99%
“…Transplantation studies and knockout mice phenotyping showed that loss of C-type γ-Pcdhs leads to increased cell death in spinal cord interneurons and cINs (Chen W. V. et al, 2012;Leon et al, 2020). Remarkably, within the C-type γ-Pcdhs, only one isoform (PcdhγC4) seems to be necessary for neuronal survival of several cell populations (Garrett et al, 2019).…”
Section: Roles In Neuronal Survivalmentioning
confidence: 99%
“…The 22 Pcdhg isoforms share an identical cytoplasmic terminus but bear unique juxtamembrane domains; both domains regulate Pcdhg trafficking (Fernandez-Monreal et al, 2009;O'Leary et al, 2011;Shonubi et al, 2015). Pcdhg-dependent survival will involve isoform-specific signalling through extracellular and juxtamembrane regions because the subset of C-type Pcdhg genes, and PcdhgC4 in particular, is essential for neuronal survival Garrett et al 2019). Diverse cPcdhs isoforms might also signal together as Pcdh-alpha and Pcdh-beta members multimerize and functionally cooperate with the Pcdhgs to contribute to neuronal survival (Goodman et al, 2017;Goodman et al, 2016;Han et al, 2009;Hasegawa et al, 2016;Ing-Esteves et al, 2018).…”
Section: The Pcdhgs Mediate a Pro-survival Mechanism For Gabaergic Inmentioning
confidence: 99%
“…Conditional deletions in the retina and spinal cord revealed that Pcdhgs mediate a survival program that follows the developmental pattern of Bax-dependent PCD (Lefebvre et al, 2008;Prasad et al, 2008). Of the twenty-two Pcdhgs, the three C-type Pcdhg genes are required for neuronal survival and a recent study of CRISPR-mediated Pcdhg deletion mutants suggests that PcdhgC4 is solely essential (Garrett et al, 2019). Constitutive Pcdha and Pcdhb mutants, on the other hand, are viable and exhibit little to no cell loss (Hasegawa et al, 2016;Ing-Esteves et al, 2018).…”
Section: Introductionmentioning
confidence: 99%
“…Knockout of the three C-type isoforms ( Pcdhγc3 - c5 ) of the Pcdh γ cluster results in neuronal apoptosis that is indistinguishable from that observed in mice with deletion of the entire Pcdh γ cluster ( Chen et al, 2012 ; Carriere et al, 2020 ; Mancia Leon et al, 2020 ). Moreover, deletion of only Pcdhγc4 fully recapitulates interneuron apoptosis caused by deletion of the entire Pcdh γ cluster, suggesting that Pcdhγc4 is the only crucial isoform required for neuronal survival ( Figure 3E ) ( Garrett et al, 2019 ). Although genetic evidence suggested that Pcdhγc4 contributes to interneuron survival, analyses of double or tri-cluster deletion mice revealed that Pcdh α and β clusters also have cooperative roles in neuronal survival.…”
Section: Biological Functions Of Clustered Pcdhsmentioning
confidence: 99%