miR-9a Minimizes the Phenotypic Impact of Genomic Diversity by Buffering a Transcription Factor

Cassidy, Justin J.; Jha, Aashish R.; Posadas, Diana M.; Giri, Ritika; Ji, Jingran; Jiang, Hongmei; Bellen, Hugo J.; White, Kevin P.; Carthew, Richard W.

doi:10.1016/j.cell.2014.04.003

Cited by 17 publications

(37 citation statements)

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“…Therefore, the genetic programming of development includes mechanisms to ensure that developmental events occur flawlessly despite stressful conditions (1,2). Several studies indicate that microRNAs (miRNAs) are used to maintain the robustness of biological processes under stress conditions (3)(4)(5)(6)(7)(8)(9)(10). miRNAs are endogenous, noncoding, small RNAs that posttranscriptionally regulate gene expression primarily through binding to the 3′UTR of target mRNAs, which results in translation inhibition and/or mRNA degradation (11).…”

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Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress

Ren

Ambros

2015

Proc. Natl. Acad. Sci. U.S.A.

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Animals maintain their developmental robustness against natural stresses through numerous regulatory mechanisms, including the posttranscriptional regulation of gene expression by microRNAs (miRNAs). Caenorhabditis elegans miRNAs of the let-7 family (let-7-Fam) function semiredundantly to confer robust stage specificity of cell fates in the hypodermal seam cell lineages. Here, we show reciprocal regulatory interactions between let-7-Fam miRNAs and the innate immune response pathway in C. elegans. Upon infection of C. elegans larvae with the opportunistic human pathogen Pseudomonas aeruginosa, the developmental timing defects of certain let-7-Fam miRNA mutants are enhanced. This enhancement is mediated by the p38 MAPK innate immune pathway acting in opposition to let-7-Fam miRNA activity, possibly via the downstream Activating Transcription Factor-7 (ATF-7). Furthermore, let-7-Fam miRNAs appear to exert negative regulation on the worm's resistance to P. aeruginosa infection. Our results show that the inhibition of pathogen resistance by let-7 involves downstream heterochronic genes and the p38 MAPK pathway. These findings suggest that let-7-Fam miRNAs are integrated into innate immunity gene regulatory networks, such that this family of miRNAs modulates immune responses while also ensuring robust timing of developmental events under pathogen stress.let-7 family microRNAs | p38 | Pseudomonas aeruginosa | developmental timing | innate immunity D uring development, animals routinely encounter environmental, physiological, and nutritional challenges that threaten to compromise the robust execution of developmental programs. Therefore, the genetic programming of development includes mechanisms to ensure that developmental events occur flawlessly despite stressful conditions (1, 2). Several studies indicate that microRNAs (miRNAs) are used to maintain the robustness of biological processes under stress conditions (3-10). miRNAs are endogenous, noncoding, small RNAs that posttranscriptionally regulate gene expression primarily through binding to the 3′UTR of target mRNAs, which results in translation inhibition and/or mRNA degradation (11). miRNAs with the same seed sequence (nucleotides 2-7 of the mature miRNA sequence), which are predicated potentially to share the same set of targets (12), are grouped into a family.The miRNA lin-4 and the miRNAs of the let-7 family (let-7-Fam) are central to the regulation of pluripotency and differentiation in many animal systems, including mammals (13-18). Four Caenorhabditis elegans let-7-Fam miRNAs, let-7, mir-48, mir-84, and mir-241, function in concert to repress key heterochronic gene targets, including daf-12, lin-41, and hbl-1, to stagespecifically regulate the timing of the hypodermal seam cell fates (16,(19)(20)(21)(22). In C. elegans, the temporal patterns of cell division and cell fate during larval development are exquisitely invariant, even though larvae develop as free-living inhabitants of a changing environment in soil and decaying plant materials.In the wild, worms...

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confidence: 99%

Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress

Ren

Ambros

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This regulation occurs through base-pairing interactions between miR-9a RNA and the 39-UTR of sens mRNA. Mutation of the miR-9a binding sites in the sens gene also produces bristle variation but is otherwise viable (Cassidy et al 2013). However, the 18-nucleotide binding site sequence is 100% conserved within the sens mRNAs of Drosophila species divergent over 45 million years.…”

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“…Selection was repeated for 15 generations. Culture conditions for the selection experiment were as described previously (Cassidy et al 2013). Comparison of one-and two-copy strains was performed by Z tests (n.s., not significant).…”

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“…When selection is repeated generation after generation and the population progressively evolves, the rate of phenotypic change approximates the contribution of genetic diversity to the variation of bristle number. In a prior study, we carried out artificial selection on Drosophila strains bearing either one or two copies of the intact mir-9a gene (Cassidy et al 2013). All strains additionally carried a hypomorphic mutation in the scute (sc) gene to generate greater baseline phenotypic diversity ( Figure S2).…”

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“…In our prior study, we selected individuals who had the greatest number of scutellar bristles (above the 50th percentile) and allowed these individuals to sire the next generation ( Figure S3). This selection was independently repeated for each replicate population and each strain (Cassidy et al 2013).mir-9a reduction does not enhance the response to selection for below-average phenotypes To estimate the proportion of phenotypic variation that is attributable to additive effects of each population's genetic diversity, we calculated the realized heritability (h 2 ) ( Figure S4). h 2 = 1 when genetic diversity perfectly dictates the observed phenotypic variation.…”

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Differential Masking of Natural Genetic Variation by miR-9a inDrosophila

2015

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Genetic variation is prevalent among individuals of the same species and yet the potential effects of genetic variation on developmental outcomes are frequently suppressed. Understanding the mechanisms that are responsible for this suppression is an important goal. Previously, we found that the microRNA miR-9a mitigates the impact of natural genetic variants that promote the development of scutellar bristles in adult Drosophila. Here we find that miR-9a does not affect the impact of genetic variants that inhibit the development of scutellar bristles. We show this using both directional and stabilizing selection in the laboratory. This specificity of action suggests that miR-9a does not interact with all functional classes of developmental genetic variants affecting sensory organ development. We also investigate the impact of miR-9a on a fitness trait, which is adult viability. At elevated physiological temperatures, miR-9a contributes to viability through masking genetic variants that hinder adult viability. We conclude that miR-9a activity in different developmental networks contributes to suppression of natural variants from perturbing development. KEYWORDS Drosophila; miRNA; heritability; sensory organs; development O RGANISMS are subject to conditions of genetic variation, and yet their morphological development is often robust to such challenges. Hence, developmental outcomes are rendered uniform even in the face of variable conditions of existence. The relationship between this developmental robustness and phenotypic variation in natural populations has long been remarked upon, and Waddington (1942) coined the word canalization to describe the process. As development becomes more robust, less phenotypic variation is observed among individuals in a population (Scharloo 1991;de Visser et al. 2003;Siegal and Leu 2014). This has implications not only for the relationship between genotype and phenotype, but also for evolution (Gibson and Wagner 2000;Gibson and Dworkin 2004;Wagner 2012). In one sense, robustness inhibits evolvability since it suppresses the phenotypic variation that selection acts upon. However, when a phenotype is robust to the effects of mutations, then genetic variation can potentially accumulate in a neutral state. This might permit a broad set of connected genotypes to express the same phenotype (Wagner 2012). Later, if canalization is impaired, the effects of the previously cryptic genetic variation are revealed as phenotypic variability. These can be subject to selection, thus enhancing evolvability.Morphological variation is a consequence of variable development between individuals. Development, in turn, is the complex outcome of dynamic interactions between regulatory molecules. Developmental dynamics have been successfully simulated by biochemical reaction network models, which vary in size, topology, and circuit composition and depend upon the specific developmental process, tissue type, and species (Kitano 2004;Stathopoulos and Levine 2005;Wunderlich and DePace 2011). Studie...

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