2019
DOI: 10.1101/739508
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CRISPR/Cas9 interrogation of the mouse Pcdhg gene cluster reveals a crucial isoform-specific role for Pcdhgc4

Abstract: 14The mammalian Pcdhg gene cluster encodes a family of 22 cell adhesion molecules, the gamma-15 Protocadherins (γ-Pcdhs), critical for neuronal survival and neural circuit formation. The extent to which 16 isoform diversity-a γ-Pcdh hallmark-is required for their functions remains unclear. We used a 17 CRISPR/Cas9 approach to reduce isoform diversity, targeting each Pcdhg variable exon with pooled 18 sgRNAs to generate an allelic series of 26 mouse lines with 1 to 21 isoforms disrupted via discrete indels 19 a… Show more

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Cited by 13 publications
(40 citation statements)
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“…We infer that isoforms C1 and C2 in the Pcdh-α cluster are not involved in the control of cIN cell death as we did not see a cIN cell death phenotype after removal of the entire α cluster. A recent study suggests that C4 is the key mediator in the regulation of neuronal cell death in the spinal cord (Garrett et al 2019). How these specific C isoforms in the Pcdh-γ cluster mediate cell death remains a fundamental question for future research.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…We infer that isoforms C1 and C2 in the Pcdh-α cluster are not involved in the control of cIN cell death as we did not see a cIN cell death phenotype after removal of the entire α cluster. A recent study suggests that C4 is the key mediator in the regulation of neuronal cell death in the spinal cord (Garrett et al 2019). How these specific C isoforms in the Pcdh-γ cluster mediate cell death remains a fundamental question for future research.…”
Section: Discussionmentioning
confidence: 99%
“…How these specific C isoforms in the Pcdh-γ cluster mediate cell death remains a fundamental question for future research. Interestingly, C4 isoform appears to be unique in that it is the only Pcdh that appears not to bind in a homophilic manner (Garrett et al 2019;Thu et al 2014). It is possible that this isoform has evolved as a general sensor of population size to adjust local circuit neuron numbers.…”
Section: Discussionmentioning
confidence: 99%
“…We studied mice in which either all variable exons of the α cluster are deleted (α-KO) or all exons of the β cluster are deleted (β-KO). We did not examine γ-cluster mutants (γ-KO) because they are perinatal lethal (Hasegawa S et al 2016;Garrett AM et al 2019;Mancia Leon WR et al 2020), before mature cIN spatial distribution is established. Since loss of a cPcdh cluster would reduce the potential pool of cPcdhs any given cell could draw from for self-and cell-cell recognition, we hypothesized that it would result in disruptions to PV and SST cell distribution.…”
Section: Loss Of α-Protocadherins Reduces the Density Of Pv Neurons Amentioning
confidence: 99%
“…They impart neurons with single cell identity by differential (and largely stochastic) expression of cPcdhs, which form combinatorial cPcdh recognition complexes (Esumi S et al 2005;Hirano K et al 2012;Brasch J et al 2019). These molecules mediate crucial circuit formation functions (Mountoufaris G et al 2017) including dendritic selfavoidance (Lefebvre JL et al 2012), axonal tiling (Chen WV et al 2017), and cell survival (Hasegawa S et al 2016;Garrett AM et al 2019). Deficits in a-cPcdh diversity can cause detectable changes in sensory processing (Yamagishi T et al 2018).…”
Section: Introductionmentioning
confidence: 99%
“…HDR uses another homologous chromosome as a template to repair gene; normally, it does not cause mutations [29]. However, NHEL has a false-prone tendency and causes unexpected base insertion of deletion at the fracture site, resulting in transcoding mutation and functional loss of the target base.9 Now, CRISPR/Cas9 technology mainly uses this feature to knock out specific DNA fragments [30]. Because of the abundance of NGG sequences in the human genome, the system can target almost any gene in human genome [31].…”
Section: Mechanism Of Crispr/cas9 Systemmentioning
confidence: 99%