ADAR1 mediated regulation of neural crest derived melanocytes and Schwann cell development

Nadjet Gacem,Sylvie Dufour,Nadege Bondurand,Stephane Mathis,Pierre De La Grange,Jean Michel Vallat,Melanie Parisot,Jeanne Amiel,Raj P Kapur,Veronique Pingault,Lisa Zerad,Laurence Richard,Anthula Kavo

doi:10.1038/s41467-019-14090-5

Abstract

The neural crest gives rise to numerous cell types, dysfunction of which contributes to many disorders. Here, we report that adenosine deaminase acting on RNA (ADAR1), responsible for adenosine-to-inosine editing of RNA, is required for regulating the development of two neural crest derivatives: melanocytes and Schwann cells. Neural crest specific conditional deletion of Adar1 in mice leads to global depigmentation and absence of myelin from peripheral nerves, resulting from alterations in melanocyte survival and differentiation of Schwann cells, respectively. Upregulation of interferon stimulated genes precedes these defects, which are associated with the triggering of a signature resembling response to injury in peripheral nerves. Simultaneous extinction of MDA5, a key sensor of unedited RNA, rescues both melanocytes and myelin defects in vitro, suggesting that ADAR1 safeguards neural crest derivatives from aberrant MDA5-mediated interferon production. We thus extend the landscape of ADAR1 function to the fields of neural crest development and disease.

Highlights

The neural crest gives rise to numerous cell types, dysfunction of which contributes to many disorders
Mutations of ADAR1 are responsible for AicardiGoutières Syndrome (AGS, OMIM: 61501013–15), an inflammatory encephalopathy referred to as a type 1 interferonopathy, and Dyschromatosis Symmetrica Hereditaria (DSH, OMIM: 12740016–18), characterized by hypo- and hyperpigmentation macules on the extremities that appear in infancy
We studied the requirement of A-to-I RNA editing in neural crest (NC) cells in vivo by breeding mice harboring a floxed Adar[1] allele with mice expressing Cre recombinase driven by the human tissue plasminogen (HtPA) promoter, triggering ablation of the floxed alleles in NC cells from E931

Summary

Introduction

The neural crest gives rise to numerous cell types, dysfunction of which contributes to many disorders. Neural crest specific conditional deletion of Adar[1] in mice leads to global depigmentation and absence of myelin from peripheral nerves, resulting from alterations in melanocyte survival and differentiation of Schwann cells, respectively. The embryonic lethality of Adar[1] mutants is rescued upon concomitant deletion of either Ifih[1] or Mavs, encoding the cytosolic dsRNA sensor MDA5 (melanoma differentiation-associated protein 5) and MAVS (mitochondrial antiviral-signaling protein), respectively[10,11,12] Overall, these data suggest that the key in vivo function of ADAR1 is to mark, via editing, endogenous dsRNAs as self and prevent their immune recognition by MDA5, safeguarding cells from unwanted MDA5-mediated IFN production and ISGs expression in a cell-type-specific manner. SCs precursors develop into immature SCs, into promyelinating SCs, which establish a one-to-one relationship with large caliber axons, before transforming into myelinforming mature SCs within the first two postnatal weeks in mice[24,25,26]

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Results

Conclusion