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

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

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

  1. Yan Zou1,
  2. Hui Chiu1,
  3. Dorothée Domenger2,3,
  4. Chiou-Fen Chuang1,*,, and
  5. Chieh Chang1,2,3,*,
  1. 1Division of Developmental Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH 45229, USA.
  2. 2Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada.
  3. 3Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 1B1, Canada.
  1. To whom correspondence should be addressed. E-mail: chieh.chang{at}cchmc.org (C.C.); chiou-fen.chuang{at}cchmc.org (C.-F.C.)
  • * 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.

Citation:

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

Developmental Decline in Neuronal Regeneration by the Progressive Change of Two Intrinsic Timers
Y. Zou, H. Chiu, A. Zinovyeva, V. Ambros, C.-F. Chuang, and C. Chang
Science 340, 372-376 (19 April 2013)

Heterochronic Genes Turn Back the Clock in Old Neurons
P. Nix, and M. Bastiani
Science 340, 282-283 (19 April 2013)

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