Clustered Protocadherins Emerge as Novel Susceptibility Loci for Mental Disorders

Jia, Zhilian; Wu, Qiang

doi:10.3389/fnins.2020.587819

Cited by 32 publications

(23 citation statements)

References 170 publications

(341 reference statements)

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“…It remains to be investigated how this is associated with the impaired motor functions, spatial learning deficits and the improved fear-context memory observed in Mphosph8 or Morc2a deficient mice. Since dysregulation of clustered protocadherins is associated with a variety of neurological and neurodevelopmental diseases as well as mental disorders including autism spectrum disorder, bipolar disorder, Alzheimer’s disease, cognitive impairments and schizophrenia 30, 31 , our data on the key importance of the HUSH complex in protocadherin gene expression might provide new understanding on the epigenetic regulation of such diseases.…”

Section: Discussionmentioning

confidence: 98%

The HUSH complex controls brain architecture and protocadherin fidelity

Hagelkrüys

Horrer

Taubenschmid-Stowers

et al. 2021

Preprint

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Fine-tuning of neural connectivity is important for cerebral functions and brain evolution. Protocadherins provide barcodes for neuronal identity as well as synapse formation and expansion of protocadherin cluster genes has been linked to advanced cognitive functions. The tightly controlled stochastic and combinatorial expression of the different protocadherin isoforms in individual neurons provides the molecular basis for neuronal diversity, neuronal network complexity and function of the vertebrate brain. How protocadherins are epigenetically controlled has not yet been fully elucidated. Here we show that the HUSH (human silencing hub) complex containing H3K9me3 binding protein M-phase phosphoprotein 8 (MPP8) and Microrchidia CW-type zinc finger protein 2 (MORC2), critically controls the fidelity of protocadherin expression. MPP8 and MORC2A are highly expressed in the murine brain and exclusively found in neurons. Genetic inactivation of Mphosph8 (coding for MPP8) or Morc2a in the nervous system of mice leads to increased brain size, altered brain architecture, and behavioral changes. Mechanistically, MPP8 and MORC2A precisely and selectively suppress the repetitive-like protocadherin gene cluster on mouse chromosome 18 in a H3K9me3-dependent manner, thereby affecting synapse formation. Moreover, we demonstrate that individual MPHOSPH8- or MORC2-deficient neurons in human cerebral organoids express increased numbers of clustered protocadherin isoforms. Our data identify the HUSH complex, previously linked to silencing of repetitive transposable elements, as a key epigenetic regulator of protocadherin expression in the nervous system and thereby brain development and neuronal individuality in mice and humans.

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Section: Discussionmentioning

confidence: 98%

The HUSH complex controls brain architecture and protocadherin fidelity

Hagelkrüys

Horrer

Taubenschmid-Stowers

et al. 2021

Preprint

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“…The clustered PCDHs participate in a wide variety of neurodevelopmental processes such as dendritic self-avoidance, axonal even spacing and tiling, spine morphogenesis and synaptogenesis, and neuronal migration and survival ( 23 , 54 ). Through stochastic and combinatorial expression, the clustered PCDH genes encode countless assemblies of cell-surface molecules to endow each neuron with a unique identity code ( 33 , 38 , 47 , 55–58 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of REST/NRSF regulation of clustered protocadherin α genes

Tang

Jia

et al. 2021

Nucleic Acids Research

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Repressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5–1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDHα genes. Thus, REST/NRSF represses PCDHα gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.

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“…The clustered Pcdh proteins are essential for self-avoidance and tiling of neuronal processes as well as proper assembly of neuronal connectivity and cortical neuron migration ( Fukuda et al, 2008 ; Garrett et al, 2012 ; Lefebvre et al, 2012 ; Suo et al, 2012 ; Chen et al, 2017 ; Fan et al, 2018 ). Their mutations or dysregulations are associated with numerous neuropsychiatric and neurodevelopmental disorders ( Flaherty and Maniatis, 2020 ; Jia and Wu, 2020 ). These Pcdhs negatively regulate CAKs Pyk2 and Fak through the cytoplasmic domains ( Chen et al, 2009 ; Garrett et al, 2012 ; Suo et al, 2012 ; Fan et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Pyk2 suppresses contextual fear memory in an autophosphorylation-independent manner

Zheng

Suo

Zhou

et al. 2021

Journal of Molecular Cell Biology

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Clustered protocadherins (Pcdhs) are a large family of cadherin-like cell adhesion proteins that are central for neurite self-avoidance and neuronal connectivity in the brain. Their downstream non-receptor tyrosine kinase Pyk2 (proline-rich tyrosine kinase 2, also known as Ptk2b, Cakb, Raftk, Fak2, and Cadtk) is predominantly expressed in the hippocampus. We constructed Pyk2 null mouse lines and found that these mutant mice showed enhancement in contextual fear memory, without any change in auditory-cued and spatial-referenced learning and memory. In addition, by preparing Y402F mutant mice, we observed that Pyk2 suppressed contextual fear memory in an autophosphorylation-independent manner. Moreover, using high-throughput RNA sequencing, we found that immediate early genes, such as Npas4, cFos, Zif268/Egr1, Arc, and Nr4a1, were enhanced in Pyk2 null mice. We further showed that Pyk2 disruption affected pyramidal neuronal complexity and spine dynamics. Thus, we demonstrated that Pyk2 is a novel fear memory suppressor molecule and Pyk2 null mice provide a model for understanding fear-related disorders. These findings have interesting implications regarding dysregulation of the Pcdh‒Pyk2 axis in neuropsychiatric disorders.

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Clustered Protocadherins Emerge as Novel Susceptibility Loci for Mental Disorders

Cited by 32 publications

References 170 publications

The HUSH complex controls brain architecture and protocadherin fidelity

The HUSH complex controls brain architecture and protocadherin fidelity

Mechanism of REST/NRSF regulation of clustered protocadherin α genes

Pyk2 suppresses contextual fear memory in an autophosphorylation-independent manner

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