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Analysis on Gene Modular Network Reveals Morphogen-Directed Development Robustness in Drosophila

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Analysis on Gene Modular Network Reveals Morphogen-Directed Development Robustness in Drosophila Zhang et al. Cell Discovery (2020) 6:43 Cell Discovery https://doi.org/10.1038/s41421-020-0173-z www.nature.com/celldisc ARTICLE Open Access Analysis on gene modular network reveals morphogen-directed development robustness in Drosophila Shuo Zhang1,2,JuanZhao1,3, Xiangdong Lv1,2, Jialin Fan1,2,YiLu1,TaoZeng 1,3, Hailong Wu1, Luonan Chen 1,3,4,5 and Yun Zhao1,4,6 Abstract Genetic robustness is an important characteristic to tolerate genetic or nongenetic perturbations and ensure phenotypic stability. Morphogens, a type of evolutionarily conserved diffusible molecules, govern tissue patterns in a direction-dependent or concentration-dependent manner by differentially regulating downstream gene expression. However, whether the morphogen-directed gene regulatory network possesses genetic robustness remains elusive. In the present study, we collected 4217 morphogen-responsive genes along A-P axis of Drosophila wing discs from the RNA-seq data, and clustered them into 12 modules. By applying mathematical model to the measured data, we constructed a gene modular network (GMN) to decipher the module regulatory interactions and robustness in morphogen-directed development. The computational analyses on asymptotical dynamics of this GMN demonstrated that this morphogen-directed GMN is robust to tolerate a majority of genetic perturbations, which has been further validated by biological experiments. Furthermore, besides the genetic alterations, we further demonstrated that this morphogen-directed GMN can well tolerate nongenetic perturbations (Hh production changes) via computational fi 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; analyses and experimental validation. Therefore, these ndings clearly indicate that the morphogen-directed GMN is robust in response to perturbations and is important for Drosophila to ensure the proper tissue patterning in wing disc. Introduction further subdivide the tissue into different regions to fulfill – All of the multicellular organisms display specific body the specific function1 3. patterns, which is a result of the systemic incorporation of Morphogens are evolutionarily conserved, diffusible and individual tissues or organs. Therefore, correct tissue long-range signaling molecules that govern the tissue patterns are essential for body pattern formation. Tissue pattern formation by regulating the expression of down- patterns are well organized in early development process stream genes in a distance-dependent and/or – in both vertebrates and invertebrates, and are mainly concentration-dependent manner1 4. Because of the dif- determined by the morphogen gradients, which could fusible property, different concentrations of morphogens thus form the morphogen gradient, which results in dif- ferential gene expression profiles carrying tissue posi- – tional information5 10. The morphogen gradient plays an Correspondence: Yun Zhao ([email protected])or indispensable role in tissue patterning and is widely Luonan Chen ([email protected]) investigated in the mouse neural tube, the limb bud, the 1State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy blastoderm, the anterior–posterior (A–P) and of Sciences, University of Chinese Academy of Sciences, 200031 Shanghai, dorsal–ventral (D–V) axes of Drosophila imaginal discs, China especially in the wing imaginal disc2,7,11. 2University of Chinese Academy of Sciences, 100049 Beijing, China Full list of author information is available at the end of the article. These authors contributed equally: Shuo Zhang, Juan Zhao © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Zhang et al. Cell Discovery (2020) 6:43 Page 2 of 14 The Drosophila wing imaginal disc is one of the most morphogen-directed gene modular network (GMN) typical models to investigate the morphogen-mediated based on the Boolean model, which is an effective – tissue patterning in development4,7,12 14. In the wing approach for inferring and analyzing biological net- imaginal disc, there exist two axes, the A–P and D–V axes works24,25. Through in silico and in vivo experiments, we (Fig. 1a)7,11,12,15. The tissue patterning of wing disc in both demonstrated that the morphogen-directed GMN is axes is precisely guided by different morphogen gradients robust in response to various genetic perturbations. and is critical for the wing growth and proper morphol- Moreover, by combining computational analyses and ogy2,16,17 (Fig. 1a, c). Generally, tissue patterning in the experimental validations, we demonstrated that this D–V direction is determined by the Wingless signaling morphogen-directed GMN can also tolerate Hh produc- whereas the Hedgehog (Hh) and Decapentaplegic (Dpp) tion changes. Interestingly, Hh production increase seems gradients play important roles in tissue patterning along more likely to be tolerated by this GMN compared to Hh the A–P direction9,13,18,19. production decrease. In wing discs, Hh is exclusively produced and post- translationally modified by adding the cholesterol and Results palmitic acid in P compartment cells7,11,12, indicating the In vivo samples acquired by Geo-seq fit the morphogen help of lipoprotein or extracellular structures in Hh gradients transport8. Previous reports have shown that Hh patterns To simplify our investigation on the morphogen- the central part of the wing7,8, and acts as a morphogen to mediated genetic robustness, we chose to analyze the A compartment cells11. When Hh diffuses into A com- PGE profiles exclusively along A–P direction. For this partment, it binds to Patched (Ptc), the receptor of Hh, purpose, we developed a GFP reporter fly(ptcGal4-uas- and alleviates the inhibition of Smoothened (Smo), and GFP) in which GFP expression is driven by patched (ptc) then Ci is changed into active form, which could activate a promoter that responds to Hh gradient. As a result, the series of downstream target genes, including dpp and ptc. cells in A/P boundary is marked with GFP (Fig. 1d–d‴). Therefore, there exists a secondary effect of Hh gradient We then collected the PGE information by adopting Geo- in wing disc patterning, which is achieved by activating seq approach26, a method combining laser capture the expression of Dpp in cells in A compartment near the microdissection27,28 with tiny-sample RNA-seq, and per- A/P boundary11. In addition, the graded upregulation of formed a series of bioinformatic analyses (Fig. 1q). To Ptc could further restrict the spread of Hh via endocy- precisely collect tissue samples along A–P direction, the tosis1. Moreover, neither the dysfunction nor over- GFP-labeled wing imaginal discs were first consecutively expression of Hh could result in normal adult wing, cut into 4 μm-thick sections via frozen section along the indicating that Hh gradient is critical for the proper wing A–P axis (Fig. 1b), and these 4 μm microdissections were disc patterning in Drosophila7,20. then subjected to precise laser capture to collect tiny In addition, organisms are always facing various genetic tissue masses from the defined section areas (Fig. 1e–k′). and/or nongenetic perturbations/alterations during the This sample collection procedure greatly ensures the PGE development and long-time evolution, which have the profiles derived from those samples faithfully reflecting potential to cause abnormality of tissue patterning and morphogen gradients along the A–P axis but not the even organism lethality21,22. To avoid those detrimental Wingless gradient along the D–V axis. Following this changes, organisms usually possess genetic robustness to sample collection procedure, we collected a set of frozen tolerate those variations to maintain the phenotypic and sections in the A/P boundary region in the direction of A functional stability21,23. Although it is well known that to P compartment and conducted the laser microdissec- those morphogen-mediated differential position-related tion to acquire the defined areas (Fig. 1e–k′). The samples gene expression (PGE) profiles form a tissue-specific gene are then named with B1–B7 sequentially according to the regulatory network to determine proper tissue pattern, position of frozen sections from A to P compartment whether morphogen-directed gene expression network (sample set B). The following qPCR assays demonstrated possesses genetic robustness remains an open question that hh was exclusively expressed in position B7 and ci without systematic investigations. expression was restricted in the region from positions B1 In the current study, we used the Drosophila wing disc to B6, indicating that position B7 is in the P compartment as a model system, in which cells established their spa- while the region
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