Disrupting the hippocampal Piwi pathway enhances contextual fear memory in mice

Leighton, Laura J.; Wei, Wei; Marshall, Paul R.; Ratnu, Vikram S.; Li, Xiang; Zajaczkowski, Esmi L.; Spadaro, Paola A.; Khandelwal, Nitin; Kumar, Arvind; Bredy, Timothy W.

doi:10.1016/j.nlm.2019.04.002

Cited by 23 publications

(27 citation statements)

References 35 publications

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“…The top DE gene, PIWIL2, is a master regulator of piRNA mediated DNA methylation and an inhibitor of retrotransposition (47,48). PIWIL2 also regulates the expression of plasticityrelated genes in the adult brain, and disruption of the piwi pathway in HC enhances contextual fear memory in mice (49). The second highest DE gene, MGARP, encodes a protein found on mitochondria that regulates mitochondrial morphology, distribution, and motility.…”

Section: Maternal Immune Activation Induces Brain Transcriptomic Chanmentioning

confidence: 99%

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates

Page

Gandal

Estes

et al. 2021

Biological Psychiatry

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Section: Maternal Immune Activation Induces Brain Transcriptomic Chanmentioning

confidence: 99%

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates

Page

Gandal

Estes

et al. 2021

Biological Psychiatry

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“…In the nematode C. elegans, the PIWI protein PRG-1 represses axonal regeneration in adult mechanosensory neurons (Kim et al, 2018). Mouse piwi orthologs (miwi genes) are expressed in the adult brain (Leighton et al, 2019), and miwi colocalizes with piRNAs to form RNP puncta in the dendrites of cultured hippocampal neurons (Lee et al, 2011). LNA-based antisense inhibition of one of these piRNAs results in a significant decrease in dendrite spine area (Lee et al, 2011).…”

Section: Osk Nos Piwi and Vasa In The Germ Linementioning

confidence: 99%

“…LNA-based antisense inhibition of one of these piRNAs results in a significant decrease in dendrite spine area (Lee et al, 2011). Further, knockdown of piwi-like genes in the mouse hippocampus affects adult behavior, as assayed in an experimental fear-conditioning paradigm (Leighton et al, 2019). In D. melanogaster, PIWI-related proteins Argonaute (Ago3) and Aubergine (Aub) are expressed at different levels in distinct subsets of neurons in the mushroom body (Perrat et al, 2013), the substrate for learning and memory within the insect brain (Heisenberg, 2003).…”

Section: Osk Nos Piwi and Vasa In The Germ Linementioning

confidence: 99%

Shared Cell Biological Functions May Underlie Pleiotropy of Molecular Interactions in the Germ Lines and Nervous Systems of Animals

2020

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Evolutionary developmental biology focuses on understanding the origin and evolution of extant biological variation, and the genetic basis for this variation. The genetic toolkit appears largely finite across animals, such that a combination of regulatory evolution, gene recruitment (co-option) and genetic modularity often allow morphological and developmental diversity to arise. Here we summarize a number of observations from across animals, which together suggest that many genes and gene product interaction "modules" originally characterized for their role in the germ line also have neural roles. We explore potential explanations for this observation, noting that in the context of the germ line, these genes appear to have molecular and biochemical properties that make them well-suited to breaking symmetry within cells. The resulting asymmetry is often caused by gene products co-localizing asymmetrically to sub-cellular, non-membrane bound, electron dense compartments known as ribonucleoprotein (RNP) granules. RNP granules contain high concentrations of translationally quiescent messenger RNAs and proteins and are thought to act as hubs of localized translational control. We propose that the use of strict translational control, which may be achieved via molecular processes important for RNP granule formation and/or small RNA-related processes, is an important property of and a commonality between the germ line and nervous tissues, and helps explain, at least in part, the close relationship between these two tissue types.

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“…These data also challenge the simple hypothesis that PIWIL2 affects gene expression only through the downstream effects on transposable elements, and suggests the possibility that PIWIL2 also may regulate the expression of downstream genes through methylation changes in MIA models. Indeed, in the adult HC, it has recently been reported that PIWIL2 regulates the expression of plasticity-related genes with disruption of the piwi pathway enhancing contextual fear memory and causing hyperactivity in mice (49).…”

Section: Discussionmentioning

confidence: 99%

“…is a master regulator of piRNA mediated DNA methylation and an inhibitor of retrotransposition (47,48). PIWIL2 also regulates the expression of plasticityrelated genes in the adult brain, and disruption of the piwi pathway in HC enhances contextual fear memory in mice (49). The second highest DE gene, MGARP, encodes a protein found on mitochondria that regulates mitochondrial morphology, distribution, and motility.…”

Section: Maternal Immune Activation Induces Brain Transcriptomic Chanmentioning

confidence: 99%

Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

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Gandal

Estes

et al. 2020

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Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates Nicholas F. AbstractBackground: Maternal immune activation (MIA) is a proposed risk factor for multiple neurodevelopmental and psychiatric disorders, including schizophrenia. However, the molecular and neurobiological mechanisms through which MIA imparts risk for these disorders remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for mechanistic dissection.Methods: We performed RNA-sequencing across four psychiatrically-relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus, and primary visual cortex) from 3.5-4-year old male MIA-exposed and control offspring-an age comparable to mid adolescence in humans. Results:We identify 266 unique genes differentially expressed (DE) in at least one brain region with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Across regions, we observed temporal and regional differences, but transcriptomic changes were largely similar across 1 st or 2 nd trimester MIA exposures, including for the top DE genes-PIWIL2 and MGARP. In addition to PIWIL2, several other known regulators of retrotransposition, as well as endogenous transposable elements were dysregulated in MIA offspring.Conclusions: Together, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.

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Disrupting the hippocampal Piwi pathway enhances contextual fear memory in mice

Cited by 23 publications

References 35 publications

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates

Shared Cell Biological Functions May Underlie Pleiotropy of Molecular Interactions in the Germ Lines and Nervous Systems of Animals

Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

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