Id2 and Id4 are not the major negative regulators of oligodendrocyte differentiation during early central nervous system development

Abstract

Myelin sheathes ensure the rapid conduction of neural impulse and provide nutritional support for neurons. Myelin sheathes are formed by differentiated oligodendrocytes (OLs) in the central nervous system. During OL development, the differentiation of oligodendrocyte progenitor cells (OPCs) into mature OLs is controlled by both positive differentiation factors (drivers) and negative regulatory factors (brakes). Previous studies have suggested Id2 and Id4 as the key negative factors for OL differentiation. However, these conclusions were mainly based on in vitro studies and the reported OL phenotype in Id4 mutants appear to be mild. In this study, we systematically investigated the in vivo function of Id2 and Id4 genes in OL differentiation in their genetic mutants and in embryonic chicken spinal cord. Our results showed that disruption of Id4 has no effect on OL differentiation and maturation, whereas Id2 mutants and Id2/Id4 compound mutants display a mild and transient precocity of OL differentiation. In agreement with these loss-of-function studies, Id2, but not Id4, is weakly expressed in OPCs. Despite their minor roles in OL differentiation, forced expression of Id2 and Id4 in embryonic chicken spinal cords strongly inhibit the differentiation of OPCs. Taken together, our detailed functional and expressional studies strongly suggest that Id2 and Id4 are not the major in vivo repressors of OPC differentiation during animal development, shedding new light on the molecular regulation of early OL development.

The committed oligodendrocyte precursor cell, a newly‐defined intermediate progenitor cell type in oligodendroglial lineage

“…It has been proposed that the inhibitory effects of GPR17 on OPC maturation are, at least partially, due to the upregulation and nuclear translocation of ID2/ID4, the potent OL differentiation inhibitors (Chen et al, 2009; Wang et al, 2001). However, a recent study demonstrated that ID2/ID4 are not expressed in OPCs during normal CNS development, and genetic disruption of both ID2 and ID4 has no or little effect on OPC generation and differentiation (Huang et al, 2022). Therefore, the precise function of GPR17 in OPC lineage progression and its working mechanism are still somewhat controversial and remain to be further clarified.…”

Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin

“…G protein-coupled receptor 17 (GPR17) can act as a downregulator of OLIG1 that negatively controls the maturation and coordinates the generation of myelinating OLs from pre-myelinating OLs through ID proteins [ 113 ]. Although overexpression of ID2 and ID4 both regulate myelin gene expression by inhibiting OLs differentiation [ 89 , 114 ], they are not the major in vivo repressors of differentiation [ 115 ]. Moreover, decreased levels of OLIG1 and myelin regulatory factor (MYRF) were observed under early growth response 1 (EGR1) and SOX11 overexpression, delineating the inhibitory action of the latest in OPCs differentiation [ 116 , 117 ].…”

Evidence That DDR1 Promotes Oligodendrocyte Differentiation during Development and Myelin Repair after Injury

“…In the central nervous system (CNS), myelin sheaths, the major component of the white matter, are elaborated by mature oligodendrocytes (OLs). Myelin plays a crucial role in the rapid and precise conduction of action potentials [ 1 , 2 , 3 , 4 ]. Increasing evidence has demonstrated that abnormal myelin development contributes to the disease pathogenesis including Alzheimer’s disease, major depression, and schizophrenia [ 5 , 6 , 7 ].…”