Overexpression of Egr1 Transcription Regulator Contributes to Schwann Cell Differentiation Defects in Neural Crest-Specific <i>Adar1</i> Knockout Mice
Lisa Zerad,
Nadjet Gacem,
Fanny Gayda,
Lucie Day,
Ketty Sinigaglia,
Laurence Richard,
Melanie Parisot,
Nicolas Cagnard,
Stephane Mathis,
Christine Bole-Feysot,
Mary A. O’Connell,
Veronique Pingault,
Emilie Dambroise,
Liam P. Keegan,
Jean Michel Vallat,
Nadege Bondurand
Affiliations
Lisa Zerad
Laboratory of Embryology and Genetics of Human Malformations, Imagine Institute, INSERM UMR 1163, Université Paris Cité, 24 Boulevard du Montparnasse, 75015 Paris, France
Nadjet Gacem
Laboratory of Embryology and Genetics of Human Malformations, Imagine Institute, INSERM UMR 1163, Université Paris Cité, 24 Boulevard du Montparnasse, 75015 Paris, France
Fanny Gayda
Laboratory of Embryology and Genetics of Human Malformations, Imagine Institute, INSERM UMR 1163, Université Paris Cité, 24 Boulevard du Montparnasse, 75015 Paris, France
Lucie Day
Laboratory of Embryology and Genetics of Human Malformations, Imagine Institute, INSERM UMR 1163, Université Paris Cité, 24 Boulevard du Montparnasse, 75015 Paris, France
Ketty Sinigaglia
Central European Institute for Technology, Masaryk University (CEITEC MU), Kamenice 735/5, 625 00 Brno, Czech Republic
Laurence Richard
Department of Neurology, Centre de Reference “Neuropathies Périphériques Rares”, CHU Limoges, 87000 Limoges, France
Melanie Parisot
Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UAR3633, Paris Descartes Sorbonne Paris Cite University, 75015 Paris, France
Nicolas Cagnard
Bioinformatics Platform, Imagine Institute, INSERM UMR 1163, 75015 Paris, France
Stephane Mathis
Department of Neurology (Nerve-Muscle Unit) and ‘Grand Sud-Ouest’ National Reference Center for Neuromuscular Disorders, CHU Bordeaux, Pellegrin Hospital, 33000 Bordeaux, France
Christine Bole-Feysot
Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UAR3633, Paris Descartes Sorbonne Paris Cite University, 75015 Paris, France
Mary A. O’Connell
Central European Institute for Technology, Masaryk University (CEITEC MU), Kamenice 735/5, 625 00 Brno, Czech Republic
Veronique Pingault
Laboratory of Embryology and Genetics of Human Malformations, Imagine Institute, INSERM UMR 1163, Université Paris Cité, 24 Boulevard du Montparnasse, 75015 Paris, France
Emilie Dambroise
Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Imagine Institute, INSERM UMR 1163, Université Paris Cité, 24 Boulevard du Montparnasse, 75015 Paris, France
Liam P. Keegan
Central European Institute for Technology, Masaryk University (CEITEC MU), Kamenice 735/5, 625 00 Brno, Czech Republic
Jean Michel Vallat
Department of Neurology, Centre de Reference “Neuropathies Périphériques Rares”, CHU Limoges, 87000 Limoges, France
Nadege Bondurand
Laboratory of Embryology and Genetics of Human Malformations, Imagine Institute, INSERM UMR 1163, Université Paris Cité, 24 Boulevard du Montparnasse, 75015 Paris, France
Adenosine deaminase acting on RNA 1 (ADAR1) is the principal enzyme for the adenosine-to-inosine RNA editing that prevents the aberrant activation of cytosolic nucleic acid sensors by endogenous double stranded RNAs and the activation of interferon-stimulated genes. In mice, the conditional neural crest deletion of Adar1 reduces the survival of melanocytes and alters the differentiation of Schwann cells that fail to myelinate nerve fibers in the peripheral nervous system. These myelination defects are partially rescued upon the concomitant removal of the Mda5 antiviral dsRNA sensor in vitro, suggesting implication of the Mda5/Mavs pathway and downstream effectors in the genesis of Adar1 mutant phenotypes. By analyzing RNA-Seq data from the sciatic nerves of mouse pups after conditional neural crest deletion of Adar1 (Adar1cKO), we here identified the transcription factors deregulated in Adar1cKO mutants compared to the controls. Through Adar1;Mavs and Adar1cKO;Egr1 double-mutant mouse rescue analyses, we then highlighted that the aberrant activation of the Mavs adapter protein and overexpression of the early growth response 1 (EGR1) transcription factor contribute to the Adar1 deletion associated defects in Schwann cell development in vivo. In silico and in vitro gene regulation studies additionally suggested that EGR1 might mediate this inhibitory effect through the aberrant regulation of EGR2-regulated myelin genes. We thus demonstrate the role of the Mda5/Mavs pathway, but also that of the Schwann cell transcription factors in Adar1-associated peripheral myelination defects.
