Two microRNA regulatory circuits set start and end times for dendritic arborization of a nociceptive neuron

Choreographic dendritic arborization takes place within a defined time frame, but the timing mechanism is currently not known. Here, we report that a precisely timed lin-4-lin-14 regulatory circuit triggers an initial dendritic growth activity whereas a precisely timed let-7-lin-41 regulatory circuit signals a subsequent developmental decline in dendritic growth ability, hence restricting dendritic arborization within a defined time frame. Loss-of-function mutations in the lin-4 microRNA gene cause limited dendritic outgrowth whereas loss-of-function mutations in its direct target, the lin-14 transcription factor gene, cause precocious and excessive outgrowth. In contrast, loss-of-function mutations in the let-7 microRNA gene prevent a developmental decline in dendritic growth ability whereas loss-of-function mutations in its direct target, the lin-41 tripartite motif protein gene, cause further decline. lin-4 and let-7 regulatory circuits are expressed at the right place and the right time to set start and end times for PVD dendritic arborization. Replacing the endogenous lin-4 promoter at the lin-4 locus with a late-onset let-7 promoter delays PVD dendrite arborization whereas replacing the endogenous let-7 promoter at the let-7 locus with an early-onset lin-4 promoter causes precocious decline in dendritic growth ability in PVD neurons. We further find that lin-28 acts upstream of let-7 in regulating developmental decline in dendritic growth ability. Our results indicate that the lin-4-lin-14 and the lin-28-let-7-lin-41 regulatory circuits control the timing of PVD dendrite arborization through antagonistic regulation of the DMA-1 receptor level on PVD dendrites.