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Whole-embryo modeling of early segmentation in Drosophila identifies robust and fragile expression domains.

ABSTRACT: Segmentation of the Drosophila melanogaster embryo results from the dynamic establishment of spatial mRNA and protein patterns. Here, we exploit recent temporal mRNA and protein expression measurements on the full surface of the blastoderm to calibrate a dynamical model of the gap gene network on the entire embryo cortex. We model the early mRNA and protein dynamics of the gap genes hunchback, Kruppel, giant, and knirps, taking as regulatory inputs the maternal Bicoid and Caudal gradients, plus the zygotic Tailless and Huckebein proteins. The model captures the expression patterns faithfully, and its predictions are assessed from gap gene mutants. The inferred network shows an architecture based on reciprocal repression between gap genes that can stably pattern the embryo on a realistic geometry but requires complex regulations such as those involving the Hunchback monomer and dimers. Sensitivity analysis identifies the posterior domain of giant as among the most fragile features of an otherwise robust network, and hints at redundant regulations by Bicoid and Hunchback, possibly reflecting recent evolutionary changes in the gap-gene network in insects.

SUBMITTER: Bieler J

PROVIDER: S-EPMC3136765 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Whole-embryo modeling of early segmentation in Drosophila identifies robust and fragile expression domains.

Bieler Jonathan J Pozzorini Christian C Naef Felix F

Biophysical journal 20110701 2

Segmentation of the Drosophila melanogaster embryo results from the dynamic establishment of spatial mRNA and protein patterns. Here, we exploit recent temporal mRNA and protein expression measurements on the full surface of the blastoderm to calibrate a dynamical model of the gap gene network on the entire embryo cortex. We model the early mRNA and protein dynamics of the gap genes hunchback, Kruppel, giant, and knirps, taking as regulatory inputs the maternal Bicoid and Caudal gradients, plus ...[more]

PMID: 21767480

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Project description:Transcranial brain stimulation (TBS) has been established as a method for modulating and mapping the function of the human brain, and as a potential treatment tool in several brain disorders. Typically, the stimulation is applied using a one-size-fits-all approach with predetermined locations for the electrodes, in electric stimulation (TES), or the coil, in magnetic stimulation (TMS), which disregards anatomical variability between individuals. However, the induced electric field distribution in the head largely depends on anatomical features implying the need for individually tailored stimulation protocols for focal dosing. This requires detailed models of the individual head anatomy, combined with electric field simulations, to find an optimal stimulation protocol for a given cortical target. Considering the anatomical and functional complexity of different brain disorders and pathologies, it is crucial to account for the anatomical variability in order to translate TBS from a research tool into a viable option for treatment. In this article we present a new method, called CHARM, for automated segmentation of fifteen different head tissues from magnetic resonance (MR) scans. The new method compares favorably to two freely available software tools on a five-tissue segmentation task, while obtaining reasonable segmentation accuracy over all fifteen tissues. The method automatically adapts to variability in the input scans and can thus be directly applied to clinical or research scans acquired with different scanners, sequences or settings. We show that an increase in automated segmentation accuracy results in a lower relative error in electric field simulations when compared to anatomical head models constructed from reference segmentations. However, also the improved segmentations and, by implication, the electric field simulations are affected by systematic artifacts in the input MR scans. As long as the artifacts are unaccounted for, this can lead to local simulation differences up to 30% of the peak field strength on reference simulations. Finally, we exemplarily demonstrate the effect of including all fifteen tissue classes in the field simulations against the standard approach of using only five tissue classes and show that for specific stimulation configurations the local differences can reach 10% of the peak field strength.

Project description:In early development, genes are expressed in spatial patterns which later define cellular identities and tissue locations. The mechanisms of such pattern formation have been studied extensively in early Drosophila (fruit fly) embryos. The gap gene hunchback (hb) is one of the earliest genes to be expressed in anterior-posterior (AP) body segmentation. As a transcriptional regulator for a number of downstream genes, the spatial precision of hb expression can have significant effects in the development of the body plan. To investigate the factors contributing to hb precision, we used fine spatial and temporal resolution data to develop a quantitative model for the regulation of hb expression in the mid-embryo. In particular, modelling hb pattern refinement in mid nuclear cleavage cycle 14 (NC14) reveals some of the regulatory contributions of simultaneously-expressed gap genes. Matching the model to recent data from wild-type (WT) embryos and mutants of the gap gene Krüppel (Kr) indicates that a mid-embryo Hb concentration peak important in thoracic development (at parasegment 4, PS4) is regulated in a dual manner by Kr, with low Kr concentration activating hb and high Kr concentration repressing hb. The processes of gene expression (transcription, translation, transport) are intrinsically random. We used stochastic simulations to characterize the noise generated in hb expression. We find that Kr regulation can limit the positional variability of the Hb mid-embryo border. This has been recently corroborated in experimental comparisons of WT and Kr- mutant embryos. Further, Kr regulation can decrease uncertainty in mid-embryo hb expression (i.e. contribute to a smooth Hb boundary) and decrease between-copy transcriptional variability within nuclei. Since many tissue boundaries are first established by interactions between neighbouring gene expression domains, these properties of Hb-Kr dynamics to diminish the effects of intrinsic expression noise may represent a general mechanism contributing to robustness in early development.

Project description:BackgroundRobustness to natural temperature fluctuations is critical to proper development in embryos and to cellular functions in adult organisms. However, mechanisms and pathways which govern temperature compensation remain largely unknown beyond circadian rhythms. Pathways which ensure robustness against temperature fluctuations may appear to be nonessential under favorable, uniform environmental conditions used in conventional laboratory experiments where there is little variation for which to compensate. The endo-siRNA pathway, which produces small double-stranded RNAs in Drosophila, appears to be nonessential for robust development of the embryo under ambient uniform temperature and to be necessary only for viral defense. Embryos lacking a functional endo-siRNA pathway develop into phenotypically normal adults. However, we hypothesized that small RNAs may regulate the embryo's response to temperature, as a ribonucleoprotein complex has been previously shown to mediate mammalian cell response to heat shock.Principal findingsHere, we show that the genes DICER-2 and ARGONAUTE2, which code for integral protein components of the endo-siRNA pathway, are essential for robust development and temperature compensation in the Drosophila embryo when exposed to temperature perturbations. The regulatory functions of DICER-2 and ARGONAUTE2 were uncovered by using microfluidics to expose developing Drosophila embryos to a temperature step, in which each half of the embryo develops at a different temperature through developmental cycle 14. Under this temperature perturbation, dicer-2 or argonaute2 embryos displayed abnormal segmentation. The abnormalities in segmentation are presumably due to the inability of the embryo to compensate for temperature-induced differences in rate of development and to coordinate developmental timing in the anterior and posterior halves. A deregulation of the length of nuclear division cycles 10-14 is also observed in dicer-2 embryos at high temperatures.ConclusionsResults presented herein uncover a novel function of the endo-siRNA pathway in temperature compensation and cell cycle regulation, and we hypothesize that the endo-siRNA pathway may regulate the degradation of maternal cell cycle regulators. Endo-siRNAs may have a more general role buffering against environmental perturbations in other organisms.

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Whole-embryo modeling of early segmentation in Drosophila identifies robust and fragile expression domains.

Publications

Whole-embryo modeling of early segmentation in Drosophila identifies robust and fragile expression domains.

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