Role of CTGF in White Matter Development in Tuberous Sclerosis
Annual rept. 1 Feb 2014-31 Jan 2015
CHILDREN'S HOSPITAL CORP BOSTON MA
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Our results show that neurons lacking Tsc1 results in a block in oligodendrocyte maturation and thus hypomyelination in the mouse brain. We show that Tsc-deficient neurons secrete excessive amounts of connective tissue growth factor CTGF, which blocks the maturation of oligodendrocytes. We show here that CTGF is both necessary and sufficient to block the oligodendrocyte maturation. To determine whether CTGF is necessary in vivo, we generated mice lacking both Tsc1 and CTGF in neurons Tsc1ccCTGFffSynCre mice. In order to investigate the effect of CTGF on oligodendrocyte maturation, we propose to treat the oligodendrocytes with different domains of CTGF Module I to IV. Moreover, in order to investigate the upstream regulation of CTGF expression in Tsc-deficient neurons, we tested Serum Response Factor SRF pathway, which was previously shown to affect CTGF expression. Our preliminary results show that SRF is downregulated in Tsc1 mutant brains and this can be rescued by rapamycin treatment suggesting a crosstalk between SRF and mTOR pathways.
- Medicine and Medical Research