The hypothalamic melanocortin system, which includes neurons that produce proopiomelanocortin (POMC)-derived peptides, is a major negative regulator of energy balance. A distinct developmental property of POMC neurons during embryonic life is that they can adopt an orexigenic neuropeptide Y (NPY) phenotype. However, the molecular mechanisms underlying cell fate decisions within immature populations of POMC neurons remain unknown. MicroRNAs (miRNAs) have recently emerged as critical regulators of brain development. These non-coding small endogenous RNA molecules have important functions in gene regulation and abnormal miRNA maturation impairs neuronal differentiation, causes cell death and disrupts axon growth. Here, we explored whether miRNAs are important components of the phenotypic maturation of POMC neurons during embryonic life. Lack of Dicer, an essential enzyme for miRNA maturation, in POMC neurons causes metabolic defects that are associated with an age-dependent reduction in the number of cells expressing Pomc mRNA. Cell lineage approaches also suggest that the loss of Dicer in Pomc-expressing progenitors favors acquisition of a non-POMC phenotype. “miRNome” microarray analysis further indicates a role for miR-103/107, specifically, in differentiating Pomc progenitors into POMC neurons versus NPY neurons. Supporting this idea, in utero and in vitro inhibition of miR-107 using antagomirs shows that loss of miR-107 expression is accompanied with an increase in the proportion of Pomc progenitors that differentiate into NPY neurons. Together, these data suggest new role for miRNAs, and particularly miR103/107, in the timely maturation of POMC neurons. They also provide new insights into the developmental mechanisms responsible for the regulation of energy balance in adults.

Supported by grants from the NIH (Grant DK84142) and The Saban Research Institute.