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Sci. Signal., 12 June 2012
Vol. 5, Issue 228, p. ra43
[DOI: 10.1126/scisignal.2002437]

RESEARCH ARTICLES

The lin-4 MicroRNA Targets the LIN-14 Transcription Factor to Inhibit Netrin-Mediated Axon Attraction

Yan Zou1, Hui Chiu1, Dorothée Domenger2,3, Chiou-Fen Chuang1*{dagger}, and Chieh Chang1,2,3*{dagger}

1 Division of Developmental Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH 45229, USA.
2 Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada.
3 Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 1B1, Canada.

* Senior authors contributed equally to this work.

Abstract: miR-125 microRNAs, such as lin-4 in Caenorhabditis elegans, were among the first microRNAs discovered, are phylogenetically conserved, and have been implicated in regulating developmental timing. Here, we showed that loss-of-function mutations in lin-4 microRNA increased axon attraction mediated by the netrin homolog UNC-6. The absence of lin-4 microRNA suppressed the axon guidance defects of anterior ventral microtubule (AVM) neurons caused by loss-of-function mutations in slt-1, which encodes a repulsive guidance cue. Selective expression of lin-4 microRNA in AVM neurons of lin-4–null animals indicated that the effect of lin-4 on AVM axon guidance was cell-autonomous. Promoter reporter analysis suggested that lin-4 was likely expressed strongly in AVM neurons during the developmental time frame that the axons are guided to their targets. In contrast, the lin-4 reporter was barely detectable in anterior lateral microtubule (ALM) neurons, axon guidance of which is insensitive to netrin. In AVM neurons, the transcription factor LIN-14, a target of lin-4 microRNA, stimulated UNC-6–mediated ventral guidance of the AVM axon. LIN-14 promoted attraction of the AVM axon through the UNC-6 receptor UNC-40 [the worm homolog of vertebrate Deleted in Colorectal Cancer (DCC)] and its cofactor MADD-2, which signals through both the UNC-34 (Ena) and the CED-10 (Rac1) downstream pathways. LIN-14 stimulated UNC-6–mediated axon attraction in part by increasing UNC-40 abundance. Our study indicated that lin-4 microRNA reduced the activity of LIN-14 to terminate UNC-6–mediated axon guidance of AVM neurons.

{dagger} To whom correspondence should be addressed. E-mail: chieh.chang{at}cchmc.org (C.C.); chiou-fen.chuang{at}cchmc.org (C.-F.C.)

Citation: Y. Zou, H. Chiu, D. Domenger, C.-F. Chuang, C. Chang, The lin-4 MicroRNA Targets the LIN-14 Transcription Factor to Inhibit Netrin-Mediated Axon Attraction. Sci. Signal. 5, ra43 (2012).

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