Overexpression of Egr1 Transcription Regulator Contributes to Schwann Cell Differentiation Defects in Neural Crest-Specific Adar1 Knockout Mice.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Schwann Cells*/metabolism ; Schwann Cells*/pathology ; Adenosine Deaminase*/genetics ; Adenosine Deaminase*/metabolism ; Cell Differentiation*/genetics ; Neural Crest*/metabolism ; Mice, Knockout*; Animals ; Mice ; Myelin Sheath/metabolism ; Interferon-Induced Helicase, IFIH1/genetics ; Interferon-Induced Helicase, IFIH1/metabolism

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 ( Adar1 cKO), we here identified the transcription factors deregulated in Adar1 cKO mutants compared to the controls. Through Adar1 ; Mavs and Adar1 cKO; 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.

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ANR-21-CE12-0020 Agence Nationale de la Recherche; AFM- 23777 AFM

Keywords: ADAR1; EGR1; MAVS; Schwann cells; differentiation; neural crest

EC 3.5.4.4 (Adenosine Deaminase)
EC 3.5.4.4 (ADAR1 protein, mouse)
EC 3.6.1.- (Ifih1 protein, mouse)
EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1)

Date Created: 20241217 Date Completed: 20241217 Latest Revision: 20250104

20250104

PMC11639873

10.3390/cells13231952

39682701