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

Megan M Nelson,Mya L Zeese,J Damon Hoff,Gabriel Corfas

doi:10.3389/fcell.2021.693595

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.

Highlights

(ADP-ribose) polymerase 1 (PARP1) is a ubiquitously expressed enzyme that plays roles in a variety of key biological processes, including DNA repair, inflammation, transcription, and programmed cell death (Kraus, 2008; Krishnakumar and Kraus, 2010; Jubin et al, 2017)
We found that the surface area of Poly (ADP-ribose) polymerase 1 (PARP1) KO brain sections tends to be smaller than their WT littermates at each level along the rostral–caudal axis, indicating that brain size is reduced overall rather than in a specific area (Figure 1E), which corresponds with a reduction in brain volume in PARP1 KO animals (Figure 1F)
To test if the increased levels of Reelin present in media conditioned by PARP1 KO neural progenitor cells (NPCs) has functional consequences, we focused on cell adhesion since a prior study showed that Reelin increases neuronal adhesion to N-cadherin using AFM

Summary

Introduction

(ADP-ribose) polymerase 1 (PARP1) is a ubiquitously expressed enzyme that plays roles in a variety of key biological processes, including DNA repair, inflammation, transcription, and programmed cell death (Kraus, 2008; Krishnakumar and Kraus, 2010; Jubin et al, 2017). PARP1 exerts its functions by protein PARylation, a post-translational modification consisting of the covalent attachment of ADP-ribose polymers (PAR) to itself and other proteins using NAD+ as PARP1 Regulates Cajal-Retzius Cell Development a donor (Krishnakumar and Kraus, 2010). Adult PARP1 KO mice have a reduced brain weight, altered neuronal proliferation within the brain’s dentate gyrus (Plane et al, 2012) and subventricular zone (Hong et al, 2019), and display schizophrenia-like behaviors, including defects in prepulse inhibition, decreased social interaction, and increased anxiety-like behaviors (Hong et al, 2019). Human studies have linked mutations in genes affecting PARylation to episodic psychosis, intellectual disability, peripheral neuropathy, ataxia, and increased risk of stroke (Najmabadi et al, 2011; Danhauser et al, 2018; Meng et al, 2018; Durmus et al, 2021)

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