Hypoxia Delays Oligodendrocyte Progenitor Cell Migration and Myelin Formation by Suppressing Bmp2b Signaling in Larval Zebrafish

Abstract

Hypoxia in newborns tends to result in developmental deficiencies in the white matter of the brain. As previous studies of the effects of hypoxia on neuronal development in rodents and human infants have been unable to use in vivo imaging, insight into the dynamic development of oligodendrocytes (OLs) in the central nervous system under hypoxia is limited. Here, we developed a visual model to study OL development using sublethal postnatal hypoxia in zebrafish larvae. We observed that hypoxia significantly suppressed OL progenitor cell migration toward the dorsum using in vivo imaging. Further, we found that hypoxia affected myelination, as indicated by thinner myelin sheaths and by a downregulation of myelin basic protein expression. Bmp2b protein expression was also significantly downregulated following hypoxia onset. Using gain of function and loss of function experiments, we demonstrated that the Bmp2b protein was associated with the regulation of OL development. Thus, our work provides a visual hypoxia model within which to observe OL development in vivo, and reveals the underlying mechanisms involved in these processes.

Fetal Zone Steroids Show Discrete Effects on Hyperoxia-Induced Attenuation of Migration in Cultured Oligodendrocyte Progenitor Cells

“…Previous reports have shown that hypoxia impairs the migration of OPCs [ 23 ]; however, not much is known about the effects of hyperoxia on the migration of OPCs and the molecular signalling involved. Therefore, in order to get a detailed insight into what happens to OPCs under hyperoxic conditions, we treated the OLN93 cells with 80% O 2 for a period of 24 hours without glucose or serum deprivation.…”

“…Myelination is achieved by extending many branched processes that wrap around the axon multiple times. But prior to the onset of myelination, newborn OL precursor cells (OPCs) undergo a phase of local proliferation followed by extensive migration to different parts of the brain from their point of origin [ 23 ]. Therefore, in a developing brain, proper myelination and remyelination are highly dependent on the capacity of OPCs to migrate to their target destinations and initiate differentiation.…”

Influenza causes alterations to oligodendrocyte-specific transcripts and the myelin lipidome in the adult mouse central nervous system.

“…Importantly other contributing factors resulting from infection likely in uence glial responses. For instance, hypoxemia is known to affect developing OLs 69,70 . Possible underlying processes are enhanced systemic in ammation and increased oxidative stress that can also occur under hypoxic conditions caused by acute respiratory infection.…”

Oxygen and the Spark of Human Brain Evolution: a Complex Systems Account

“…On one end, relatively higher oxygen tension seems to favour the growth of neurons and oligodendrocytes, with consequent increase in intracortical myelination, which is most pronounced at lower levels of the human cortical hierarchy (Burt et al, 2018). Relatively lower oxygen tension instead seems to rebalance the cell milieu away from myelinating oligodendrocytes and towards astrocytes (Xie et al, 2014, Yang et al, 2018 which support glucose transport and metabolism (Pellerin and Magistretti, 1994). Thus, by regulating the type of cells that develop in a given region, oxygen tension contributes to establish higher aerobic glycolysis at the top of the hierarchy, and higher myelination at the opposite (lower) end of the hierarchy.…”