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

The GABA_A receptor (GABA_AR) 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 GABA_AR 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_AR protein but had no effect on GABA_AR mRNA. Moreover, Mn upregulated the levels of FTO and inhibited global cellular m⁶A levels and GABA_Aα2 mRNA m⁶A levels. Knockdown of FTO increased the expression of GABA_AR protein and GABA_Aα2 mRNA m⁶A levels. Data from rat models further demonstrate that inhibition of FTO suppressed GABA_AR protein expression in the hypothalamus, causing delayed puberty onset. Collectively, our findings suggest that FTO-dependent m⁶A demethylation plays a critical role in regulating GABA_AR mRNA processing in GnRH neurons.