Two intrinsic timing mechanisms set start and end times for dendritic arborization of a nociceptive neuron.

Abstract

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