These results favor the idea that HBL-1 acts autonomously in both

These results favor the idea that HBL-1 acts autonomously in both VD and DD neurons. HBL-1 expression could reprogram VD neurons to adopt the DD cell fate, MK 2206 thereby causing ectopic expression of the remodeling program. This scenario seems unlikely because bidirectional changes in hbl-1 expression produce corresponding shifts in the timing of DD plasticity. If HBL-1 were inducing the DD cell fate, we would not expect HBL-1 expression to bidirectionally alter the timing

of DD remodeling. HBL-1 activity could accelerate DD remodeling by regulating expression of factors that directly mediate synapse elimination and formation. Finally, HBL-1 could be part of a timing mechanism that dictates when remodeling occurs. The effects of UNC-55 orthologs (COUP-TFs and Sevenup) and an

HBL-1 ortholog (Hb) on developmental timing in flies and mice provide support for HBL-1 function as part of a conserved timing mechanism. Ultimately, identifying the relevant HBL-1 transcriptional OSI-744 nmr targets will be required to distinguish between these models. Many aspects of early neuronal development are regulated by microRNAs (e.g., neuronal fate determination, neural tube closure, and mitotic exit) (Fineberg et al., 2009 and Fiore et al., 2008). microRNAs have also been implicated in the functional plasticity of mature circuits (Fineberg et al., 2009, Fiore et al., 2008 and Simon et al., 2008). Our results show that microRNAs play an important role in restricting when plasticity

occurs during development. In particular, we show that miR-84 regulates the timing of DD plasticity, and that it does so by regulating hbl-1. The Drosophila microRNA Let-7 plays a similar role in dictating the timing of NMJ growth during larval development ( Sokol et al., 2008 and Caygill and Johnston, 2008). It is interesting that Let-7 and miR-84 are paralogs that bind to related seed sequences in target mRNAs. Thus, Let-7 microRNAs (and their targets) represent an ancient mechanism for determining the timing of circuit development. Perhaps the most surprising aspect of our results is that the timing of DD plasticity is regulated by activity. not Mutations increasing and decreasing circuit activity had opposite effects on the timing of DD plasticity. These results are significant because they suggest that DD plasticity (and other forms of genetically programmed plasticity) and activity-dependent circuit refinement are not necessarily distinct processes, and may utilize similar genetic pathways. In this context, it is noteworthy that all of the genetic factors we identify (UNC-55/COUP-TF, HBL-1, and miR-84) are conserved in vertebrates, and vertebrate orthologs are all expressed in the CNS. It will be interesting to see if these molecules also play a role in refining vertebrate circuits. Several forms of plasticity are triggered by changes in the activity of the postsynaptic targets.

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