Single-cell gene expression profile of the postnatal mouse arcuate nucleus in the hypothalamus

m6A, the most prevalent internal modification on mRNAs, plays important roles in the nervous system. Whether neurogenesis in the hypothalamus, a region critical for controlling appetite, is regulated by m6A signaling, especially in humans, remains unclear. Here we showed that deletion of m6A writer Mettl14 in the mouse embryonic hypothalamus led to adult obesity, with impaired glucose-insulin homoeostasis and increased energy intake. Mechanistically, deletion of Mettl14 leads to hypothalamic arcuate nucleus neurogenesis deficits with reduced generation of feeding-related neurons and dysregulation of neurogenesis-related m6A-tagged transcripts. Deletion of m6A writer Mettl3, or m6A reader Ythdc1, shared similar phenotypes. METTL14 or YTHDC1 knockdown also led to reduced generation of feeding-related neurons in human brain subregion-specific arcuate nucleus organoids. Our studies reveal a conserved role of m6A signaling in arcuate nucleus neurogenesis in mice and human organoids and shed light on the developmental basis of epitranscriptomic regulation of food intake and energy homeostasis.N6-甲基腺嘌呤（m6A）是信使RNA（mRNA）上最为普遍的内部修饰类型，在神经系统中发挥关键调控作用。下丘脑作为调控食欲的核心脑区，其神经发生过程是否受m6A信号调控，尤其是在人类中，目前仍未明确。本研究证实，在小鼠胚胎下丘脑中敲除m6A写入酶Mettl14，会导致成年小鼠出现肥胖表型，伴随葡萄糖-胰岛素稳态受损与能量摄入增加。机制层面，Mettl14的敲除会引发下丘脑弓状核的神经发生缺陷，表现为进食相关神经元的生成量减少，以及神经发生相关的带有m6A修饰的转录本调控紊乱。敲除m6A写入酶Mettl3或m6A读取蛋白Ythdc1，均可观察到相似的表型。在人类脑区特异性弓状核类器官中，敲低METTL14或YTHDC1同样会降低进食相关神经元的生成水平。本研究揭示了m6A信号在小鼠及人类类器官的弓状核神经发生中具有保守作用，并为表观转录组调控进食行为与能量稳态的发育机制提供了新的研究视角。