FIGURE 9.

Hypothetical model for FA-mediated rescue of stem cell proliferation and neurogenesis. Pax3 mutant “Splotch” homozygous embryos do not express functional Pax3, which leads to up-regulation of several miRNAs during early cell proliferation stages, some of which target H3K27 histone demethylase KDM6B. This results in decreased KDM6B expression and increased H3K27 methylation. The association between methylated H3K27 and the Hes1 promoter results in (a) decreased Hes1 expression and lowered stem cell proliferation. At the same time low association between methylated H3K27 and the Neurog2 promoter, but high association between acetylated H3K9 and H3K18 and the Neurog2 promoter results in (b) premature neurogenesis. FA-mediated rescue could be due to reversible down-regulation of KDM6B targeting micro-RNAs, resulting in up-regulation of KDM6B and subsequent lowering of H3K27 methylation. Demethylated H3K27 shows decreased binding to the Hes1 promoter and increased binding to the Neurog2 promoter, which results in (c) increased stem cell proliferation/maintenance and (d) normal neurogenesis.