Poly (ADP-Ribose) Polymerase 1 Regulates Cajal–Retzius Cell Development and Neural Precursor Cell Adhesion

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) is a ubiquitously expressed enzyme that regulates DNA damage repair, cell death, inflammation, and transcription. PARP1 functions by adding ADP-ribose polymers (PAR) to proteins including itself, using NAD+ as a donor. This post-translational modification known as PARylation results in changes in the activity of PARP1 and its substrate proteins and has been linked to the pathogenesis of various neurological diseases. PARP1 KO mice display schizophrenia-like behaviors, have impaired memory formation, and have defects in neuronal proliferation and survival, while mutations in genes that affect PARylation have been associated with intellectual disability, psychosis, neurodegeneration, and stroke in humans. Yet, the roles of PARP1 in brain development have not been extensively studied. We now find that loss of PARP1 leads to defects in brain development and increased neuronal density at birth. We further demonstrate that PARP1 loss increases the expression levels of genes associated with neuronal migration and adhesion in the E15.5 cerebral cortex, including Reln. This correlates with an increased number of Cajal–Retzius (CR) cells in vivo and in cultures of embryonic neural progenitor cells (NPCs) derived from the PARP1 KO cortex. Furthermore, PARP1 loss leads to increased NPC adhesion to N-cadherin, like that induced by experimental exposure to Reelin. Taken together, these results uncover a novel role for PARP1 in brain development, i.e., regulation of CR cells, neuronal density, and cell adhesion.

Effect of Nicotinamide Mononucleotide Concentration in Human Milk on Neurodevelopmental Outcome: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study

“…Important processes in human neurodevelopment that occur during the first two years of life include neuronal proliferation, axon and dendrite growth, synapse formation, and myelination [ 44 , 45 ], and all of these processes can involve NAD synthase or NAD+-dependent enzymes. For instance, NAMPT is associated with neural stem cell proliferation [ 53 ]; PARP1 is associated with neuronal proliferation, migration, and adhesion [ 54 ]; NMNAT is associated with dendrite and axon elongation and branching [ 55 , 56 , 57 , 58 ]; SIRT2 is associated with neuronal migration and dendritic development and myelination [ 59 , 60 , 61 ]; and SIRT6 is associated with dendrite development [ 62 ]. NMN in human milk could affect infant development through these processes.…”

Whole Genome Sequencing Revealed Inherited Rare Oligogenic Variants Contributing to Schizophrenia and Major Depressive Disorder in Two Families

“…Among them, PARP1 and ZBTB16 were implicated in the pathogenesis of schizophrenia. Parp1-deficient mice showed defective neurogenesis and maldevelopment of the brain, and manifested schizophrenia-like behavior [82,83]. Zbtb16-deficient mice showed social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment [84].…”

NAD+-Consuming Enzymes in Stem Cell Homeostasis

“…PARylation is reported to promote the proliferation and self-renewal of mouse brain NSCs by inhibiting p53 activation [ 81 ]. PARP1 loss leads to defects in brain development, increased neuronal density at birth in mice, and enhanced embryonic NSC adhesion to N-cadherin in vitro [ 82 ].…”