A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans

Abstract

Animal development is remarkably robust; cell fates are specified with spatial and temporal precision despite physiological and environmental contingencies. Favorable conditions cause Caenorhabditis elegans to develop rapidly through four larval stages (L1-L4) to the reproductive adult. In unfavorable conditions, L2 larvae can enter the developmentally quiescent, stress-resistant dauer larva stage, enabling them to survive for prolonged periods before completing development. A specific progression of cell division and differentiation events occurs with fidelity during the larval stages, regardless of whether an animal undergoes continuous or dauer-interrupted development. The temporal patterning of developmental events is controlled by the heterochronic genes, whose products include microRNAs (miRNAs) and regulatory proteins. One of these proteins, the DAF-12 nuclear hormone receptor, modulates the transcription of certain let-7-family miRNAs, and also mediates the choice between the continuous vs. dauer-interrupted life history. Here, we report a complex feedback loop between DAF-12 and the let-7-family miRNAs involving both the repression of DAF-12 by let-7-family miRNAs and the ligandmodulated transcriptional activation and repression of the let-7-Fam miRNAs by DAF-12. We propose that this feedback loop functions to ensure robustness of cell fate decisions and to coordinate cell fate with developmental arrest.gene regulation ͉ microRNA ͉ nuclear hormone receptor T he complexity of animal development requires the coordination of temporal, spatial, and physiological cues. Successful development is necessary to achieve optimal fitness, and natural selection has favored developmental programs that robustly produce a desired outcome in a range of physiological and environmental conditions. Forward genetics has revealed much of the internal programming of several developmental processes in standardized laboratory conditions. A fundamental question emerging from these studies is how these genetic circuits are affected by conditions that are more similar to natural, variable environments. Caenorhabditis elegans has been an excellent system to uncover developmental mechanisms because of its well-defined cell lineage and tractability to genetic analysis. C. elegans development is robust in a wide range of environmental conditions, providing an excellent opportunity to determine how genetic pathways are modulated in these diverse environments (1).There are two distinct life histories a C. elegans larva may follow: a rapid, continuous life history that occurs in favorable environments and an extended, interrupted life history (2) that occurs in response to increased population density, decreasing food supplies, and elevated temperature (Fig. 1) (3). Within the continuous life history, animals progress through four larval stages (L1-L4) to a reproductively competent adult within Ϸ40-50 h after hatching (4). By contrast, unfavorable environments sensed during L1 stage cause larvae to enter the predauer L2d stage, which is ...

The Developmental Timing Regulatorhbl-1Modulates the Dauer Formation Decision inCaenorhabditis elegans

“…This idea is consistent with the model that TGFb and IIS pathways affect daf-9 expression, which eventually translates into altered levels of DA and an effect on DAF-12 activity (Gerisch et al 2001;. During the L2d stage, the let-7-family microRNAs and LIN-42/Period fine-tune DAF-12 expression and activity, respectively, permitting high sensitivity to environmental conditions (Hammell et al 2009;Tennessen et al 2010). In wild-type larvae, the final decision to commit to dauer diapause is made during the early L2d molt (Golden and Riddle 1984).…”

“…This was based on the finding that certain daf-12 alleles cause the inappropriate reiteration of L2 cell fates in L3-staged larvae (Antebi et al 1998). More recently, additional genes that regulate the L2 vs. L3 cell fate decision have been shown to influence the dauer formation decision (Hammell et al 2009;Tennessen et al 2010). hbl-1 promotes L2 cell fates and inhibits L3 cell fates, downstream from other known L2 vs. L3 cell fate regulators (Abrahante et al 2003;Lin et al 2003;Abbott et al 2005;Bethke et al 2009;Hammell et al 2009).…”

“…Dafachronic acid was provided by David Mangelsdorf (University of Texas Southwestern Medical Center, Dallas, TX). Experiments were performed as described (Hammell et al 2009). Strains: AA199 daf-9(dh6); dhEx24[daf-91, sur-5TGFP] and VT1996 hbl-1(ve18) daf-9(dh6); dhEx24 .…”

Caenorhabditis elegans period homolog lin-42 regulates the timing of heterochronic miRNA expression

“…The RNA-binding protein LIN-28 negatively regulates let-7 by blocking processing, a function that is conserved in mammals (9-13). In addition, transcription factors encoded by the heterochronic genes daf-12 and hbl-1 have been implicated in modulating miRNA transcription (14)(15)(16). However, given the complex temporal expression patterns of heterochronic miRNA genes, there are likely to be other factors involved in this process.…”

“…Loss of lin-42 function causes a precocious heterochronic phenotype in which the adult hypodermal program occurs one stage too early, as opposed to the reiteration of larval programs observed in miRNA mutants. In addition, lin-42 acts antagonistically to daf-12 to time cell fate decisions, and one role of daf-12 is to augment expression of let-7 family miRNAs (14,15), suggesting that lin-42 might oppose miRNA function.…”