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Remyelination is critical for nerve regeneration. However, the molecular mechanism involved in remyelination is poorly understood. To explore the roles of 17β-estradiol (E2) for myelination in the peripheral nervous system, we used a co-culture model of rat dorsal root ganglion (DRG) explants and Schwann cells (SCs) and a regeneration model of the crushed sciatic nerves in ovariectomized (OVX) and non-ovariectomized (non-OVX) rats for in vitro and in vivo analysis. E2 promoted myelination by facilitating the differentiation of SCs in vitro, which could be inhibited by the estrogen receptors (ER) antagonist ICI182780, ERβ antagonist PHTPP, or ERK1/2 antagonist PD98059. This suggests that E2 accelerates SC differentiation via the ERβ-ERK1/2 signaling. Furthermore, E2 promotes remyelination in crushed sciatic nerves of both OVX and non-OVX rats. Interestingly, E2 also significantly increased the expression of the lysosome membrane proteins LAMP1 and myelin protein P0 in the regenerating nerves. Moreover, P0 has higher degree of colocalization with LAMP1 in the regenerating nerves. Taking together, our results suggest that E2 enhances Schwann cell differentiation and further myelination via the ERβ-ERK1/2 signaling and that E2 increases the expression of myelin proteins and lysosomes in SCs to promotes remyelination in regenerating sciatic nerves.

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Motivation: Identification of disease-related genes using high-throughput microarray data is more difficult for complex diseases as compared with monogenic ones. We hypothesized that an endophenotype derived from transcriptional data is associated with a set of genes corresponding to a pathway cluster. We assumed that a complex disease is associated with multiple endophenotypes and can be induced by their up/downregulated gene expression patterns. Thus, a neural network model was adopted to simulate the gene–endophenotype–disease relationship in which endophenotypes were represented by hidden nodes.Results: We successfully constructed a three-endophenotype model for Taiwanese hypertensive males with high identification accuracy. Of the three endophenotypes, one is strongly protective, another is weakly protective and the third is highly correlated with developing young-onset male hypertension. Sixteen of the involved 101 genes were highly and consistently influential to the endophenotypes. Identification of SLC4A5, SLC5A10 and LDOC1 indicated that sodium/bicarbonate transport, sodium/glucose transport and cell-proliferation regulation may play important upstream roles and identification of BNIP1, APOBEC3F and LDOC1 suggested that apoptosis, innate immune response and cell-proliferation regulation may play important downstream roles in hypertension. The involved genes not only provide insights into the mechanism of hypertension but should also be considered in future gene mapping endeavors.Availability: Microarray data and test program are available at http://ms.iis.sinica.edu.tw/microarray/index.htmContact: pan@ibms.sinica.edu.tw or hsu@iis.sinica.edu.twSupplementary information: Supplementary data are available at Bioinformatics online.