Dataset Information

Characterization of PARP-6 function in knock out mice and patients with developmental delay

ABSTRACT: PARP-6, a member of a family of enzymes (17 in humans) known as poly-ADP- ribose polymerases (PARPs), is a neuronally enriched PARP. While previous studies from our group show that PARP-6 is a regulator of dendrite morphogenesis in hippocampal neurons, its function in the nervous system in vivo is poorly understood. Here, we describe the generation of a PARP-6 loss-of-function mouse model for examining the function of PARP-6 during neurodevelopment in vivo. Using CRISPR-Cas9 mutagenesis, we generated a mouse line that expresses a PARP-6 truncated variant (PARP-6TR) in place of PARP-6WT. Unlike PARP-6WT, PARP-6TR is devoid of catalytic activity. Homozygous PARP-6TR do not exhibit obvious neuromorphological defects during development, but nevertheless die perinatally. This suggests that PARP-6 catalytic activity is important for postnatal survival. We also report PARP-6 mutations in six patients with several neurodevelopmental disorders, including microencephaly, intellectual disabilities, and epilepsy. The most severe mutation in PARP-6 (C563R) results in the loss of catalytic activity. Expression of the PARP-6C563R mutant in hippocampal neurons decreases dendrite morphogeneis. Taken together, these results suggest that PARP-6 is an essential gene in mice, and the loss of PARP-6 catalytic activity has detrimental effects on neuronal function in humans.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Neuron

SUBMITTER: Phillip Wilmarth

LAB HEAD: Michael S. Cohen

PROVIDER: PXD025386 | Pride | 2021-07-21

REPOSITORIES: Pride

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Publications

Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay.

Vermehren-Schmaedick Anke A Huang Jeffrey Y JY Levinson Madison M Pomaville Matthew B MB Reed Sarah S Bellus Gary A GA Gilbert Fred F Keren Boris B Heron Delphine D Haye Damien D Janello Christine C Makowski Christine C Danhauser Katharina K Fedorov Lev M LM Haack Tobias B TB Wright Kevin M KM Cohen Michael S MS

Cells 20210522 6

PARP6, a member of a family of enzymes (17 in humans) known as poly-ADP-ribose polymerases (PARPs), is a neuronally enriched PARP. While previous studies from our group show that Parp6 is a regulator of dendrite morphogenesis in rat hippocampal neurons, its function in the nervous system in vivo is poorly understood. Here, we describe the generation of a <i>Parp6</i> loss-of-function mouse model for examining the function of Parp6 during neurodevelopment in vivo. Using CRISPR-Cas9 mutagenesis, w ...[more]

PMID: 34067418

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Project description:Many of the long-term effects of cocaine on the brain's reward circuitry have been shown to be mediated by alterations in gene expression. Several chromatin modifications, including histone acetylation and methylation, have been implicated in this regulation, but the effect of other histone modifications remains poorly understood. Poly(ADP-ribose) polymerase-1 (PARP-1), a ubiquitous and abundant nuclear protein, catalyzes the synthesis of a negatively charged polymer called poly(ADP-ribose) or PAR on histones and other substrate proteins and forms transcriptional regulatory complexes with several other chromatin proteins. Here, we identify an essential role for PARP-1 in cocaine-induced molecular, neural, and behavioral plasticity. Repeated cocaine administration, including self-administration, increased global levels of PARP-1 and its mark PAR in mouse nucleus accumbens (NAc), a key brain reward region. Using PARP-1 inhibitors and viral-mediated gene transfer, we established that PARP-1induction in NAc mediates enhanced behavioral responses to cocaine, including increased self-administration of the drug. Using chromatin immunoprecipitation sequencing, we demonstrated a global, genome-wide enrichment of PARP-1 in NAc of cocaine-exposed mice and identified several PARP-1 target genes that could contribute to the lasting effects of cocaine. Specifically, we identified sidekick-1-important for synaptic connections during development-as a critical PARP-1 target gene involved in cocaine's behavioral effects as well as in its ability to induce dendritic spines on NAc neurons. These findings establish the involvement of PARP-1 and PARylation in the long-term actions of cocaine. c57bl/6 mice were given IP injections of chronic cocaine 20mg/kg once per day for 7 days and sacrificed 30 minutes after the final dose of cocaine. Control animals were given saline for 7 days and sacrificed 30 minutes after the final dose of saline. Nucleus accumbens (NAc) tissue was collected and then PARP-1 ChIP-seq was performed. Three sequencing replicates were performed on each group.

Dataset Information

Characterization of PARP-6 function in knock out mice and patients with developmental delay

Publications

Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay.

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