Regulation of Caenorhabditis elegans neuronal polarity by heterochronic genes

Many neurons display characteristic patterns of synaptic connections that are under genetic control. The Caenorhabditis elegans 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 blmp-1 transcription factor gene, the lin-29/Zn finger transcription factor, lin-28/RNA binding protein, and the let-7miRNA gene all disrupt the presynaptic polarity of this DA cholinergic neuron. We also show that the dre-1/F box heterochronic gene functions early in development to control maintenance of polarity at later stages, and that a mutation in the let-7 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.

A network of heterochronic genes including Imp1 regulates temporal changes in stem cell properties

Stem cell properties change over time to match the changing growth and regeneration demands of tissues. We showed previously that adult forebrain stem cell function declines during aging because of increased expression of let-7 microRNAs, evolutionarily conserved heterochronic genes that reduce HMGA2 expression. Here we asked whether let-7 targets also regulate changes between fetal and adult stem cells. We found a second let-7 target, the RNA binding protein IMP1, that is expressed by fetal, but not adult, neural stem cells. IMP1 expression was promoted by Wnt signaling and Lin28a expression and opposed by let-7 microRNAs. Imp1-deficient neural stem cells were prematurely depleted in the dorsal telencephalon due to accelerated differentiation, impairing pallial expansion. IMP1 post-transcriptionally inhibited the expression of differentiation-associated genes while promoting the expression of self-renewal genes, including Hmga2. A network of heterochronic gene products including Lin28a, let-7, IMP1, and HMGA2 thus regulates temporal changes in stem cell properties.