Despite their opposing actions on food intake, POMC and NPY/AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) are derived from the same progenitors that give rise to ARH neurons. However, the mechanism whereby common neuronal precursors subsequently adopt either the anorexigenic (POMC) or the orexigenic (NPY/AgRP) identity remains elusive. We hypothesize that POMC and NPY/AgRP cell fates are specified and maintained by distinct intrinsic factors. In search of them, we profiled the transcriptomes of developing POMC and NPY/AgRP neurons in mice. Moreover, cell-type-specific transcriptomic analyses revealed transcription regulators that are selectively enriched in either population, but whose developmental functions are unknown in these neurons. Among them, we found the expression of the PR domain-containing factor 12 (Prdm12) was enriched in POMC neurons but absent in NPY/AgRP neurons. To study the role ofPrdm12 in vivo,we developed and characterized a floxedPrdm12allele. Selective ablation ofPrdm12in embryonic POMC neurons led to significantly reducedPomcexpression as well as early-onset obesity in mice of either sex that recapitulates symptoms of human POMC deficiency. Interestingly, however, specific deletion ofPrdm12in adult POMC neurons showed that it is no longer required forPomcexpression or energy balance. Collectively, these findings establish a critical role forPrdm12in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis. Finally, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the hypothalamus whose neurodevelopment remains poorly studied.SIGNIFICANCE STATEMENTPOMC and NPY/AgRP neurons are derived from the same hypothalamic progenitors but have opposing effects on food intake. We profiled the transcriptomes of genetically labeled POMC and NPY/AgRP neurons in the developing mouse hypothalamus to decipher the transcriptional codes behind the versus orexigenic neuron identity. Our analyses revealed 29 transcription regulators that are selectively enriched in one of the two populations. We generated new mouse genetic models to selective ablate one of POMC-neuron enriched transcription factorsPrdm12in developing and adult POMC neurons. Our studies establish a previously unrecognized role forPrdm12in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis.
