RT Journal Article
SR Electronic
T1 Transcriptomic Profiling of Developing Melanocortin Neurons Reveals a Role for Prdm12 in Energy Balance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 753434
DO 10.1101/753434
A1 Xiameng Chen
A1 Steven C. Wyler
A1 Li Li
A1 Amanda G. Arnold
A1 Rong Wan
A1 Pin Xu
A1 Chen Liu
YR 2019
UL http://biorxiv.org/content/early/2019/09/03/753434.abstract
AB The hypothalamus is a critical regulator of many physiological processes essential for life. In the adult brain, each anatomically-defined hypothalamic nucleus consists of functionally heterogeneous neuronal subpopulations that dictate distinct survival behaviors. Nevertheless, how rich neuronal identities are established in the developing hypothalamus remains poorly understood.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 with whole-genome RNA sequencing (RNA-seq). 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 was absent in NPY/AgRP neurons. Selective ablation of Prdm12 in postmitotic POMC neurons led to early-onset obesity, accelerated linear growth, as well as impaired glucose tolerance, which recapitulates symptoms of POMC/MC4R deficiency in humans. These findings, therefore, establish a previously-unrecognized role for Prdm12 in energy balance. Furthermore, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the developing hypothalamus as well as the developmental origins of diverse survival behaviors.