Fateful Feedback

Abstract

Control of cell differentiation is thought to result from bistable regulatory networks that allow a transient developmental signal to cause cells to permanently adopt a differentiated state. In the nematode Caenorhabditis elegans , Johnston et al. examined such a network that determines the alternative fates of two taste receptor neurons, known as ASE left (ASEL) and ASE right (ASER). These neurons are bilaterally symmetrical but express distinct sets of chemoreceptors that are necessary for the worm's navigation in search of food. The authors find through genetic analysis that two key transcriptions factors, DIE-1 and COG-1, which promote expression of genes specific to ASEL and ASER neurons, respectively, act in a feedback loop in which they are linked by two microRNAs encoded by the lsy-6 and mir-273 genes. Expression of lsy-6 is enhanced by DIE-1 transcription factor, and the lsy-6 miRNA inhibits expression of ASER-promoting factor COG-1. COG-1 in turn promotes the expression of mir-273 miRNA, which inhibits expression of the ASEL-inducing gene die-1 . Although the stimulus that causes switching of this loop to favor production of one or the other transcription factor remains unknown, the results provide the essence of a miRNA-containing transcriptional feedback loop that can account for the stabilized expression of terminal cell fate in the ASER and ASEL neurons. R. J. Johnston Jr., S. Chang, J. F. Etchberger, C. O. Ortiz, O. Hobert, MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. Proc. Natl. Acad. Sci. U.S.A. 102 , 12449-12454 (2005). [Abstract] [Full Text]