The m 6 A mRNA demethylase FTO regulates GnRH secretion in Mn-induced precocious puberty

The GABA receptor (GABA R) plays important roles in the regulation of Mn-induced GnRH secretion in immature female rats. However, the underlying molecular mechanisms remain unknown. Here, we assessed whether FTO and its substrate m A are correlated with GABA R expression in GnRH neurons after treatment with Mn in vitro and in vivo. Our study indicated that Mn treatment increased the expression of GnRH mRNA and decreased the levels of GABA R protein but had no effect on GABA R mRNA. Moreover, Mn upregulated the levels of FTO and inhibited global cellular m A levels and GABA α2 mRNA m A levels. Knockdown of FTO increased the expression of GABA R protein and GABA α2 mRNA m A levels. Data from rat models further demonstrate that inhibition of FTO suppressed GABA R protein expression in the hypothalamus, causing delayed puberty onset. Collectively, our findings suggest that FTO-dependent m A demethylation plays a critical role in regulating GABA R mRNA processing in GnRH neurons.