| Summary: | 博士 === 國立臺灣大學 === 化學研究所 === 105 === Gene expression noise has been observed in the single-cell level, and it’s been studied in the heterogeneity among cells. How such heterogeneity contributes to the phenotypic variations is not clear. Using experimental and computational approaches, we studied the gene expression noise and phenotypic variations of distal tip cells (DTCs) migration in C. elegans. We identified the gene regulatory network that regulates the expression of unc-5 receptor, which spatiotemporally control the dorsalward migration of DTC at the third larva stage. To simulate the DTC migration timings, the regulatory logics in gene regulation were determined. We found that the interlinked feed-forward loops in the network is able to filter noises regardless of the input signals’ states. To test the hypothesis that noise contributes to phenotypic variations in mutants, we simulated stochastic unc-5 expression with its gene regulatory network. In parallel, unc-5 mRNA and protein in single DTC was quantified. Our results showed that the unc-5 transcription is too noisy to directly link to DTC migration phenotype, and suggested that DTC dorsalward turning time is determined by the level of UNC-5 protein reaching a threshold. We successfully determined a UNC-5 threshold in mathematical model and reproduced the DTC migration phenotypes in wild type and mutants. An unexpected retarded DTC migration phenotype in dre-1 mutants was predicted in our model, and further validated by experiments. Both experiments and simulations indicated that blmp-1 can activate lin-29 expression to enhance UNC-5 expression exceeding the threshold. In the blmp-1;daf-12 mutants with heterogeneous phenotypes, UNC-5 is produced near the threshold, and its expression noise brings UNC-5 above or below the threshold, generating phenotypic variations. Suppressing the upstream gene noise reduces heterogeneity in this mutant. Our work reveals a novel mechanism where dynamics and noise together lead to phenotypic variations.
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