Study The Function Of ITPR2 And TAPP1 On Oligodendrocyte Differentiation And Myelination

Myelination of neuronal axons in the central nervous system(CNS)by oligodendrocytes(OLs)enables rapid saltatory conductance and axonal integrity,which are crucial for normal brain functioning.Abnormal OLs and myelin sheath results in the demyelinating diseases and neuropsychiatry disorders such as major depression disease and schizophrenia.Mounting evidence suggests that axonal myelination is orchestrated by the intercellular signaling between neuronal axons and OLs.However,the molecular mechanisms underlying the axonal-glial interactions in CNS myelin development remain elusive.Our previous studies have found that two candidate genes Itpr2 and TAPP1 that are involved in phosphoinositol signaling pathway participate in the OLs differentiation and axonal myelination process.In the present study,we focus on their roles in OLs development and myelination.Our studies revealed that the intracellular Ca²⁺release channel associated receptor(Itpr2)is drastically up-regulated in differentiating oligodendrocytes.Functional analyses in both conventional and conditional Itpr2mutant mice demonstrated that Itpr2 deficiency affected intracellular calcium release,and caused a developmental delay of OLs differentiation in the white matter of CNS coupled with enhanced oligodendrocyte progenitor cells(OPCs)proliferation.Moreover,the Itpr2 mutation increased the percentage of small-diameter myelinated axons and altered myelin structures as well as the conduction velocity of the optic nerve.The abnormal myelin development in the mutants appeared to be caused by an increased proportion of type I/II oligodendrocytes which prefer to wrap the small diameter axons.Together,our studies indicated that Itpr2 signaling plays a vital role in regulating oligodendrocyte proliferation,differentiation and myelination during early CNS development,and Itpr2 can influence the composition of myelination in postnatal brain tissue.Considering that Itpr2 is involved in the depression,our results suggested change of microenviroment surrounding oligodendrocytes may contribute to the development of neuropsychiatry disorder.In addition,we investigated the role of TAPP1 in myelin sheath formation.Our preliminary study has indicated that TAPP1 is selectively expressed in the differentiating oligodendrocytes,and deleting TAPP1 promotes the differentiation of oligodendrocytes.By contrast,overexpressing TAPP1 inhibited the differentiation of oligodendrocytes.In our study,we overexpressed TAPP1 in premylinating oligodendrocytes with Tet-off system.Consistent with the in vitro results,it delayed OLs differention and down-regulated the expression of myelin-related genes as well as phosphorylated Erk1/2 in the spinal cords.In LPC induced demyelinated lesion,knockout of TAPP1 gene enhanced axonal remyelination.Unexpectedly,TAPP1mutation had little effect on OLs differentiation and developmental myelination,suggesting a possible functional redundancy from some unidentified related molecules.Together,our studies strongly suggested that TAPP1 functions as a negative regulator to inhibit OLs differentiation and axonal remyelination through a PI3K-Erk dependent pathway.