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Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay
Anke Vermehren-Schmaedick1,2, Jeffrey Y Huang3, Madison Levinson3
1Hospital & Specialty Medicine, VA Portland Health Care System, Portland, OR 97239, USA.
Insights
Poly-ADP-ribose polymerase 6 (PARP6) is crucial for neuronal development and survival. Loss of PARP6 catalytic activity in mice and humans leads to neurodevelopmental disorders and perinatal death.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Poly-ADP-ribose polymerase 6 (PARP6) is a neuronally enriched enzyme.
- Previous studies suggest PARP6 regulates dendrite morphogenesis in vitro.
- The in vivo function of PARP6 in the nervous system remains largely unknown.
Purpose of the Study:
- To investigate the in vivo function of PARP6 during neurodevelopment.
- To characterize a novel Parp6 loss-of-function mouse model.
- To explore the role of PARP6 in human neurodevelopmental disorders.
Main Methods:
- Generation of a Parp6 loss-of-function mouse model using CRISPR-Cas9.
- Analysis of Parp6 truncated variants (Parp6TR) and mutations (C563R).
- BioID proximity labeling and proteomics in hippocampal neurons.
Main Results:
- Parp6 loss-of-function mice die perinatally, indicating essential catalytic activity for survival.
- PARP6 mutations are associated with human neurodevelopmental disorders like microcephaly and epilepsy.
- Loss of PARP6 catalytic activity impairs dendrite morphogenesis and identifies microtubule-binding proteins.
Conclusions:
- PARP6 catalytic activity is essential for postnatal survival in mice.
- PARP6 is a critical microtubule-regulatory gene.
- Disruption of PARP6 function has severe consequences for neuronal development and function in both mice and humans.
Abstract:
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 Parp6 loss-of-function mouse model for examining the function of Parp6 during neurodevelopment in vivo. Using CRISPR-Cas9 mutagenesis, we generated a mouse line that expressed a Parp6 truncated variant (Parp6TR) in place of Parp6WT. Unlike Parp6WT, Parp6TR is devoid of catalytic activity. Homozygous Parp6TR do not exhibit obvious neuromorphological defects during development, but nevertheless die perinatally. This suggests that Parp6 catalytic activity is important for postnatal survival. We also report PARP6 mutations in six patients with several neurodevelopmental disorders, including microencephaly, intellectual disabilities, and epilepsy. The most severe mutation in PARP6 (C563R) results in the loss of catalytic activity. Expression of Parp6C563R in hippocampal neurons decreases dendrite morphogenesis. To gain further insight into PARP6 function in neurons we also performed a BioID proximity labeling experiment in hippocampal neurons and identified several microtubule-binding proteins (e.g., MAP-2) using proteomics. Taken together, our results suggest that PARP6 is an essential microtubule-regulatory gene in mice, and that the loss of PARP6 catalytic activity has detrimental effects on neuronal function in humans.
