Myelinating cells synthesize large amounts of membrane protein through the secretory pathway, which makes these cells particularly sensitive to perturbations of the endoplasmic reticulum (ER). Ig binding protein (BiP), also known as glucose-regulated protein 78 (GRP78), is a critical ER chaperone that also plays a pivotal role in controlling the cellular response to ER stress. To examine the potential importance of BiP to myelinating cells, we used a conditional knock-out approach to BiP gene inactivation in oligodendrocytes during development, in adulthood, and in response to experimental autoimmune encephalomyelitis (EAE), an animal model of the inflammatory demyelinating disorder multiple sclerosis (MS). During development, mice lacking functional BiP gene expression in oligodendrocytes developed tremors and ataxia and died before reaching maturity. When BiP gene inactivation in oligodendrocytes was initiated in adulthood, the mice displayed severe neurological symptoms including tremors and hind-limb paralysis. The inactivation of BiP in oligodendrocytes during development or in adulthood resulted in oligodendrocyte loss and corresponding severe myelin abnormalities. Mice heterozygous for the oligodendrocyte-specific inactivation of BiP, which were phenotypically normal without evidence of neuropathology, displayed an exacerbated response to EAE that correlated with an increased loss of oligodendrocytes. Furthermore, mice in which the BiP gene was specifically inactivated in developing Schwann cells displayed tremor that progressed to hindlimb paralysis, which correlated with diminished numbers of myelinating Schwann cells and severe PNS hypomyelination. These studies demonstrate that BiP is critical for myelinating cell survival and contributes to the protective response of oligodendrocyte against inflammatory demyelination.

SIGNIFICANCE STATEMENT The myelinating cells, oligodendrocytes in the CNS and Schwann cells in the PNS, are responsible for synthesizing an enormous amount of cellular membrane during the active phase of myelination. Therefore, these cells are particularly sensitive to insults that disrupt the function of the secretory pathway. Here, we show that the endoplasmic reticulum (ER) resident chaperone protein Ig binding protein (BiP) plays an essential role in the survival and function of myelinating cells both during the myelination process and in adult animals. Moreover, we demonstrate that BiP participates in the protective response of oligodendrocytes to inflammatory demyelinating insults. The work described here suggests that a compromised response to perturbations to the ER could contribute to myelin disorders of the CNS and PNS.