Isoform requirement of clustered protocadherin for preventing neuronal apoptosis and neonatal lethality

Kobayashi, Hiroaki; Takemoto, Kenji; Sanbo, Makoto; Hirabayashi, Masumi; Hirabayashi, Takahiro; Hirayama, Teruyoshi; Kanazawa, Hiroshi; Abe, Takaya; Yagi, Takeshi

doi:10.1016/j.isci.2022.105766

Cited by 8 publications

(6 citation statements)

References 51 publications

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“…While our data suggest that Pcdhγ diversity is dispensable for cIN survival, the diversity requirements for clustered Pcdhs in the Pcdha and Pcdhb clusters was not studied here: in all genotypes examined, these clusters remained intact. A recent study found that mutant mice lacking all call Pcdha, Pcdhb , and A- and B-type Pcdhg genes (thus retaining only Pcdhγc3, Pcdhγc4, and Pcdhγc5), also exhibited neonatal lethality and increased neuronal apoptosis (Kobayashi et al, 2023). These results are consistent with previous reports showing that Pcdhγc4 (uniquely among Pcdhγ isoforms) requires other “carrier” cPcdhs to be transported to the cell-surface (Thu et al 2014).…”

Section: Discussionmentioning

confidence: 99%

The Clustered Gamma Protocadherin Pcdhγc4 Isoform Regulates Cortical Interneuron Programmed Cell Death in the Mouse Cortex

Leon¹,

Steffen²,

Dale-Huang³

et al. 2023

Preprint

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Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Previously, we showed that loss of clustered gamma protocadherins (Pcdhγ), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Here we show that the sole deletion of the Pcdhγc4 isoform, but not of the other 21 isoforms in the Pcdhγ gene cluster, increased cIN cell death in mice during the normal period of programmed cell death. Viral expression of the Pcdhγc4 isoform rescued transplanted cINs lacking Pcdhγ from cell death. We conclude that Pcdhγ, specifically Pcdhγc4, plays a critical role in regulating the survival of cINs during their normal period of cell death. This demonstrates a novel specificity in the role of Pcdhγ isoforms in cortical development.

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Section: Discussionmentioning

confidence: 99%

The Clustered Gamma Protocadherin Pcdhγc4 Isoform Regulates Cortical Interneuron Programmed Cell Death in the Mouse Cortex

Leon¹,

Steffen²,

Dale-Huang³

et al. 2023

Preprint

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“…This observation could be explained by non-mutually exclusive scenarios: 1) the formation of PcdhγC4 heterodimers, in cis , with members of Pcdha and/or Pcdhb clusters, providing cellular specificity important for cIN survival; and/or 2) that PcdhγC4 (uniquely among Pcdhγ isoforms) requires other clustered Pcdhs to be transported to the cell surface ( 46 ). While the mutant mice used by Kobayahsi et al (45) retain PcdhγC3 and PcdhγC5, these isoforms are expressed at low levels in cINs. In addition, it has been shown that cis -interactions among C-type Pcdhγs are weak and this may prevent PcdhγC3 and PcdhγC5 from functioning as carriers for PcdhγC4 ( 47 ).…”

Section: Discussionmentioning

confidence: 95%

“…While our data suggest that Pcdhγ diversity is dispensable for cIN survival, the Pcdha and Pcdhb gene clusters remained intact and these Pcdhs could have contributed to diversity. A recent study found that mutant mice lacking all Pcdha, Pcdhb, and A- and B-type Pcdhγ genes (thus retaining only PcdhγC3, PcdhγC4, and PcdhγC5), also exhibited neonatal lethality and increased neuronal apoptosis ( 45 ) . This observation could be explained by non-mutually exclusive scenarios: 1) the formation of PcdhγC4 heterodimers, in cis , with members of Pcdha and/or Pcdhb clusters, providing cellular specificity important for cIN survival; and/or 2) that PcdhγC4 (uniquely among Pcdhγ isoforms) requires other clustered Pcdhs to be transported to the cell surface ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex

Leon,

Steffen,

Dale-Huang

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into the cortex where they make connections with locally produced excitatory glutamatergic neurons. Cortical function critically depends on the number of cINs, which is also key to establishing the appropriate inhibitory/excitatory balance. The final number of cINs is determined during a postnatal period of programmed cell death (PCD) when ~40% of the young cINs are eliminated. Previous work shows that the loss of clustered gamma protocadherins (Pcdhgs), but not of genes in the Pcdha or Pcdhb clusters, dramatically increased BAX-dependent cIN PCD. Here, we show that PcdhγC4 is highly expressed in cINs of the mouse cortex and that this expression increases during PCD. The sole deletion of the PcdhγC4 isoform, but not of the other 21 isoforms in the Pcdhg gene cluster, increased cIN PCD. Viral expression of the PcdhγC4, in cIN lacking the function of the entire Pcdhg cluster, rescued most of these cells from cell death. We conclude that PcdhγC4 plays a critical role in regulating the survival of cINs during their normal period of PCD. This highlights how a single isoform of the Pcdhg cluster, which has been linked to human neurodevelopmental disorders, is essential to adjust cIN cell numbers during cortical development.

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“…Excessive spinal interneuron apoptosis preceding neonatal lethality in mice lacking all 22 Pcdhg genes indicates the importance of these molecules in organismal survival (Lefebvre et al, 2008; Mancia Leon et al, 2024; Prasad et al, 2008; Wang et al, 2002). In the CNS, loss of all γ-Pcdhs or disruption of normal γ-Pcdh repertoire consistently leads to disrupted neurodevelopment, including reduced dendritic arborization, loss of dendrite and axon self-avoidance, aberrant axon coalescence, and/or altered synapse formation/maturation depending upon the neuronal cell type (Garrett et al, 2012; Garrett & Weiner, 2009; Ing-Esteves et al, 2018; Kobayashi et al, 2023; Kostadinov & Sanes, 2015; Lefebvre et al, 2012; Molumby et al, 2017; Molumby et al, 2016; Mountoufaris et al, 2017; Prasad & Weiner, 2011; Steffen et al, 2021; Weiner et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

A C-terminal motif containing a PKC phosphorylation site regulates γ-Protocadherin-mediated dendrite arborization in the cerebral cortexin vivo

Hanes,

Mah,

Steffen

et al. 2024

Preprint

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The Pcdhg gene cluster encodes 22 γ-Protocadherin (γ-Pcdh) cell adhesion molecules that critically regulate multiple aspects of neural development, including neuronal survival, dendritic and axonal arborization, and synapse formation and maturation. Each γ-Pcdh isoform has unique protein domains--a homophilically interacting extracellular domain and a juxtamembrane cytoplasmic domain--as well as a C-terminal cytoplasmic domain shared by all isoforms. The extent to which isoform-specific vs. shared domains regulate distinct γ-Pcdh functions remains incompletely understood. Our previous in vitro studies identified PKC phosphorylation of a serine residue within a shared C-terminal motif as a mechanism through which γ-Pcdh promotion of dendrite arborization via MARCKS is abrogated. Here, we used CRISPR/Cas9 genome editing to generate two new mouse lines expressing only non-phosphorylatable γ-Pcdhs, due either to a serine-to-alanine mutation (PcdhgS/A) or to a 15-amino acid C-terminal deletion resulting from insertion of an early stop codon (PcdhgCTD). Both lines are viable and fertile, and the density and maturation of dendritic spines remains unchanged in both PcdhgS/A and PcdhgCTD cortex. Dendrite arborization of cortical pyramidal neurons, however, is significantly increased in both lines, as are levels of active MARCKS. Intriguingly, despite having significantly reduced levels of γ-Pcdh proteins, the PcdhgCTD mutation yields the strongest phenotype, with even heterozygous mutants exhibiting increased arborization. The present study confirms that phosphorylation of a shared C-terminal motif is a key γ-Pcdh negative regulation point, and contributes to a converging understanding of γ-Pcdh family function in which distinct roles are played by both individual isoforms and discrete protein domains.

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Isoform requirement of clustered protocadherin for preventing neuronal apoptosis and neonatal lethality

Cited by 8 publications

References 51 publications

The Clustered Gamma Protocadherin Pcdhγc4 Isoform Regulates Cortical Interneuron Programmed Cell Death in the Mouse Cortex

The Clustered Gamma Protocadherin Pcdhγc4 Isoform Regulates Cortical Interneuron Programmed Cell Death in the Mouse Cortex

The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex

A C-terminal motif containing a PKC phosphorylation site regulates γ-Protocadherin-mediated dendrite arborization in the cerebral cortexin vivo

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