Role Of The Down Syndrome Cell Adhesion Factor Dscam On Myelin Development

Myelin sheath is an insulating membrane structure formed by mature oligodendrocytes surrounding axons,which plays an important role in maintaining the skip conduction of the action potential.Myelin abnormalities are associated with many diseases,such as multiple sclerosis,Alzheimer’s disease,autism,bipolar disorder,and schizophrenia,among others.Oligodendrocytes are originated from oligodendrocyte precursor cells,through a tightly regulated developmental process that requires the integration of multiple extracellular signals and the coordination of multiple intrinsic pathways.The Down syndrome cell adhesion factor Dscam(Down syndrome cell adhesion factor)is located on human chromosome 21 and is considered as a high-risk gene for Down syndrome and autism.It is known that Dscam plays important roles in the processes including neuronal migration,axon orientation,dendrite recognition and self-avoidance,while it also participates in the regulation of related functions in the motor cortex.It has been shown that Dscam is highly expressed in oligodendrocyte precursor cells,however the function of Dscam in cell development and myelination of the oligodendrocyte lineage remains elusive.In this paper,we will study the effects of Dscam on the oligodendrocyte lineage progression and myelination,and its possible related molecular mechanisms.We used Cre conditional knockout mice Pdgfrα-cre Dscam(f/f)and Plp-cre ER Dscam(f/f)to specifically knockout Dscam on oligodendrocyte progenitors and oligodendrocytes,respectively,to investigate the role of Dscam in mice myelin development by immunoblotting,immunohistochemistry,transmission electron microscopy,and behaviors.The results show that: 1)Dscam is highly expressed in primary oligodendrocyte precursor cells,and it is expressed in the mouse corpus callosum and correlated with myelin development.2)Pdgfrα-cre Dscam(f/f)mice showed decreased number of oligodendrocyte progenitors in the corpus callosum,increased mature oligodendrocytes,and increased expression levels of myelin-specific proteins MBP and PLP,and impaired motor coordination and diminished social cognition.3)In Plp-cre ER Dscam(f/f)mice,myelin specific protein MBP expression was downregulated.It was showed demyelination,with thinner myelin thickness.It also showed decreased total cell number of oligodendroglial lineage cells,and impaired social movement.Our study identified that Dscam plays an important role during myelin development.The absence of Dscam in oligodendrocyte cells causes changes in the expression of a series of related proteins.This suggests that in the CNS,Dscam is involved in myelination at different stages of oligodendrocyte development through different regulatory modes.This provides the experimental basis,research strategies and potential therapeutic targets for the study of oligodendrocytes and myelin-related diseases.