Regulation of <i>Caenorhabditis elegans</i> neuronal polarity by heterochronic genes.

Abstract

Many neurons display characteristic patterns of synaptic connections that are under genetic control. The <i>Caenorhabditis elegans</i> DA cholinergic motor neurons form synaptic connections only on their dorsal axons. We explored the genetic pathways that specify this polarity by screening for gene inactivations and mutations that disrupt this normal polarity of a DA motorneuron. A RAB-3::GFP fusion protein that is normally localized to presynaptic terminals along the dorsal axon of the DA9 motorneuron was used to screen for gene inactivations that disrupt the DA9 motorneuron polarity. This screen identified heterochronic genes as major regulators of DA neuron presynaptic polarity. In many heterochronic mutants, presynapses of this cholinergic motoneuron are mislocalized to the dendrite at the ventral side: inactivation of the <i>blmp-1</i> transcription factor gene, the <i>lin-29</i>/Zn finger transcription factor, <i>lin-28/</i>RNA binding protein, and the <i>let-7</i>miRNA gene all disrupt the presynaptic polarity of this DA cholinergic neuron. We also show that the <i>dre-1/</i>F box heterochronic gene functions early in development to control maintenance of polarity at later stages, and that a mutation in the <i>let-7</i> heterochronic miRNA gene causes dendritic misplacement of RAB-3 presynaptic markers that colocalize with muscle postsynaptic terminals ectopically. We propose that heterochronic genes are components in the UNC-6/Netrin pathway of synaptic polarity of these neurons. These findings highlight the role of heterochronic genes in postmitotic neuronal patterning events.