Neuronal Ndrg4 Is Essential for Nodes of Ranvier Organization in Zebrafish

Abstract

Axon ensheathment by specialized glial cells is an important process for fast propagation of action potentials. The rapid electrical conduction along myelinated axons is mainly due to its saltatory nature characterized by the accumulation of ion channels at the nodes of Ranvier. However, how these ion channels are transported and anchored along axons is not fully understood. We have identified N-myc downstream-regulated gene 4, ndrg4, as a novel factor that regulates sodium channel clustering in zebrafish. Analysis of chimeric larvae indicates that ndrg4 functions autonomously within neurons for sodium channel clustering at the nodes. Molecular analysis of ndrg4 mutants shows that expression of snap25 and nsf are sharply decreased, revealing a role of ndrg4 in controlling vesicle exocytosis. This uncovers a previously unknown function of ndrg4 in regulating vesicle docking and nodes of Ranvier organization, at least through its ability to finely tune the expression of the t-SNARE/NSF machinery.

NDRG4 promotes myogenesis via Akt/CREB activation

“…The proliferation rate of A10 cells is significantly decreased after overexpression of NDRG4 [ 40 ]. Schwann cell proliferation does not significantly differ between NDRG4 morphant embryos and controls throughout development [ 41 ]. Here, we first confirmed that NDRG4 is a positive regulator of myogenic differentiation, but NDRG4 has no effects on myoblast proliferation and the cell cycle.…”

Nervous NDRGs: the N-myc downstream–regulated gene family in the central and peripheral nervous system

“…Only recently, the function of NDRG4 in the nervous system has been investigated showing that ndrg4 plays a prominent role in signal transduction via myelinated axons in zebrafish [48]. Ndrg4-deficiency impaired the physiological function of the nodes of Ranvier, which cluster sodium channels to ensure fast transduction.…”

“…Defective vesicle docking due to ndrg4 knockdown was at least partially responsible for the impaired sodium channel clustering. Ndrg4 thus functions in vesicle release and plays a fundamental role in the development and organization of myelination in the peripheral nervous system in zebrafish [48].…”

GPR56/ADGRG1 regulates development and maintenance of peripheral myelin

“…Interestingly, although we observed no overt changes in Na + channel structure by teased nerve analysis ( Fig. 7, A and B ), we detected a significant increase in the expression of genes related to K + channel activity on P21 and a significant decrease in the expression of the Na + channel clustering protein Ndrg4 ( Fontenas et al, 2016 ) on both P3 and P21 (Fig. S3, C and D).…”