The Makorin lep-2 and the lncRNA lep-5 regulate lin-28 to schedule sexual maturation of the C. elegans nervous system

Abstract

Sexual maturation must occur on a controlled developmental schedule. In mammals, Makorin3 (<i>MKRN3</i>) and the miRNA regulators <i>LIN28A/B</i> are key regulators of this process, but how they act is unclear. In <i>C. elegans</i>, sexual maturation of the nervous system includes the functional remodeling of postmitotic neurons and the onset of adult-specific behaviors. Here, we find that the <i>lin-28-let-7</i> axis (the 'heterochronic pathway') determines the timing of these events. Upstream of <i>lin-28</i>, the Makorin <i>lep-2</i> and the lncRNA <i>lep-5</i> regulate maturation cell-autonomously, indicating that distributed clocks, not a central timer, coordinate sexual differentiation of the <i>C. elegans</i> nervous system. Overexpression of human <i>MKRN3</i> delays aspects of <i>C. elegans</i> sexual maturation, suggesting the conservation of Makorin function. These studies reveal roles for a Makorin and a lncRNA in timing of sexual differentiation; moreover, they demonstrate deep conservation of the <i>lin-28-let-7</i> system in controlling the functional maturation of the nervous system.