RT Journal Article SR Electronic T1 Imbalance of Neuregulin1-ErbB2/3 signaling underlies altered myelin homeostasis in models of Charcot-Marie-Tooth disease type 4H JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.01.20.477077 DO 10.1101/2022.01.20.477077 A1 Lara El-Bazzal A1 Adeline Ghata A1 Clothilde Estève A1 Patrice Quintana A1 Nathalie Roeckel-Trévisiol A1 Frédérique Lembo A1 Nicolas Lenfant A1 Andre Mégarbané A1 Jean-Paul Borg A1 Nicolas Lévy A1 Marc Bartoli A1 Yannick Poitelon A1 Pierre L. Roubertoux A1 Valérie Delague A1 Nathalie Bernard-Marissal YR 2022 UL http://biorxiv.org/content/early/2022/01/22/2022.01.20.477077.abstract AB Charcot Marie Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells (SC) of the peripheral nervous system, and caused by more than 100 genes. We previously identified mutations in FGD4, as responsible for CMT4H, an autosomal recessive demyelinating form of CMT. FGD4 encodes FRABIN a GDP/GTP nucleotide exchange factor (GEF), particularly for the small GTPase cdc42. Remarkably, nerves from patients with CMT4H display excessive redundant myelin called outfoldings that arise from focal hypermyelination, suggesting that FRABIN could play a role in the control of PNS myelination. To gain insights into the role of FGD4/FRABIN in SC myelination, we generated a knock-out mouse model, with conditional ablation of fgd4 in SC. We showed that the specific deletion of FRABIN in SCs leads to aberrant myelination in vitro, in dorsal root ganglion (DRG)/SCs cocultures as well in vivo, in distal sciatic nerves. We observed that those myelination defects are related to an upregulation of some interactors of the NRG1 type III/ErbB2/3 signaling pathway, which is known to ensure a proper level of myelination in the PNS. Based on a yeast two-hybrid screen, we identified SNX3 as a new partner of FRABIN, which is involved in the regulation of endocytic trafficking. Interestingly, we showed that loss of FRABIN impairs endocytic trafficking which may contribute to the defective NRG1 type III/ErbB2/3 signaling and myelination. Finally, we showed that the reestablishment of proper levels of the NRG1 type III/ErbB2/3 pathway using Niacin treatment reduces myelin outfoldings in nerves of CMT4H mice. Overall, our work reveals a new role of FRABIN in the regulation of NRG1 type III/ErbB2/3 NRG1signaling and myelination and opens future therapeutic strategies based on the modulation of NRG1 type III/ErbB2/3 NRG1to reduce CMT4H pathology and more generally others demyelinating CMT.Competing Interest StatementThe authors have declared no competing interest.