The m6A mRNA demethylase FTO regulates GnRH secretion in Mn-induced precocious puberty.

The GABAA receptor (GABAAR) 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 m6A are correlated with GABAAR 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 GABAAR protein but had no effect on GABAAR mRNA. Moreover, Mn upregulated the levels of FTO and inhibited global cellular m6A levels and GABAAα2 mRNA m6A levels. Knockdown of FTO increased the expression of GABAAR protein and GABAAα2 mRNA m6A levels. Data from rat models further demonstrate that inhibition of FTO suppressed GABAAR protein expression in the hypothalamus, causing delayed puberty onset. Collectively, our findings suggest that FTO-dependent m6A demethylation plays a critical role in regulating GABAAR mRNA processing in GnRH neurons.