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Common Mechanisms Across Mouse, Stickleback Fish, and Honey Bee Neuromolecular responses to social challenge: Common mechanisms across mouse, stickleback fish, and honey bee Clare C. Rittschofa,b,c,d,1, Syed Abbas Bukharia,e,2, Laura G. Sloofmana,f,2, Joseph M. Troya,e,2, Derek Caetano-Anollésa,g, Amy Cash-Ahmeda,b, Molly Kenta,c, Xiaochen Lua,g, Yibayiri O. Sanogoa,h, Patricia A. Weisnera,c, Huimin Zhanga,g, Alison M. Bella,c,i,j, Jian Maa,k, Saurabh Sinhaa,b,l, Gene E. Robinsona,b,c,j,1, and Lisa Stubbsa,c,g,1 aInstitute for Genomic Biology, Departments of bEntomology, gCell and Developmental Biology, iAnimal Biology, kBioengineering, and lComputer Science, cNeuroscience Program, eIllinois Informatics Institute, fCenter for Biophysics and Computational Biology, and jProgram in Ecology, Evolution, and Conservation Biology, University of Illinois at Urbana–Champaign, Urbana, IL 61801; dDepartment of Entomology, The Pennsylvania State University, University Park, PA 16802; and hGenomics Core, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH 44195 Contributed by Gene E. Robinson, October 24, 2014 (sent for review September 17, 2014; reviewed by Darcy Kelly and Kevin P. White) Certain complex phenotypes appear repeatedly across diverse contexts for and frequency of social interaction, the sensory mo- species due to processes of evolutionary conservation and conver- dalities used to perceive the social landscape, and the structure and gence. In some contexts like developmental body patterning, there function of the brain and endocrine systems that regulate behavior. is increased appreciation that common molecular mechanisms un- Nonetheless, due to genetic orthology and striking general simi- derlie common phenotypes; these molecular mechanisms include larities in certain social behaviors, it is possible that shared genes, highly conserved genes and networks that may be modified by gene networks, or functional processes have been reused to regu- lineage-specific mutations. However, the existence of deeply con- late presumably independent evolutions of certain types of social served mechanisms for social behaviors has not yet been demon- behavior across diverse species. strated. We used a comparative genomics approach to determine We used a comparative transcriptomic approach to determine whether shared neuromolecular mechanisms could underlie behav- whether shared neuromolecular mechanisms govern the response EVOLUTION ioral response to territory intrusion across species spanning a broad to an acute social challenge. We focused on a single context, the phylogenetic range: house mouse (Mus musculus), stickleback fish response to territory intrusion, which is biologically relevant for (Gasterosteus aculeatus), and honey bee (Apis mellifera). Territory our focal species and is also generalizable to many other species. intrusion modulated similar brain functional processes in each spe- We evaluated mechanistic commonalities across a phylogenetic cies, including those associated with hormone-mediated signal distance that spans ∼650 My of evolution, comparing three species transduction and neurodevelopment. Changes in chromosome or- with different ecologies and social organization: the house mouse ganization and energy metabolism appear to be core, conserved (male Mus musculus) and stickleback fish (male Gasterosteus processes involved in the response to territory intrusion. We also aculeatus), both of which are strongly territorial and somewhat found that several homologous transcription factors that are typi- social, and the highly social honey bee (female Apis mellifera cally associated with neural development were modulated across all three species, suggesting that shared neuronal effects may involve Significance transcriptional cascades of evolutionarily conserved genes. Further- more, immunohistochemical analyses of a subset of these transcrip- In some cases similar molecular programs (i.e., conserved genes tion factors in mouse again implicated modulation of energy and gene networks) underlie the expression of phenotypic traits metabolism in the behavioral response. These results provide sup- that evolve repeatedly across diverse species. We investigated port for conserved genetic “toolkits” that are used in independent this possibility in the context of social behavioral response, using evolutions of the response to social challenge in diverse taxa. a comparative genomics approach for three distantly related species: house mouse (Mus musculus), stickleback fish (Gaster- genetic hotspot | NF-κB signaling | brain metabolism | aggression osteus aculeatus), and honey bee (Apis mellifera). An experience of territory intrusion modulated similar brain functional pro- imilar phenotypes can have a shared molecular basis, even cesses across species, including hormone-mediated signal trans- Samong distantly related species (1–3). This phenomenon has duction, neurodevelopment, chromosome organization, and been observed for an array of traits, including morphological energy metabolism. Several homologous transcription factors adaptations like coat color or wing patterning, rapid adaptations also responded consistently to territory intrusion, suggesting like drug resistance, and artificially selected phenological traits like that shared neuronal effects may involve transcriptional cas- flowering time (reviewed in ref. 2). Shared molecular mechanisms cades of evolutionarily conserved genes. These results indicate “ ” can arise convergently as a result of de novo mutations at genetic that conserved genetic toolkits are involved in independent hotspots (2) or as a result of conservation. Both of these processes evolutions of social behavior. result in “genetic toolkits” or genes that are repeatedly used over Author contributions: C.C.R., A.M.B., J.M., S.S., G.E.R., and L.S. designed research; C.C.R., evolutionary time to give rise to similar phenotypes (3). The D.C.-A., A.C.-A., M.K., X.L., Y.O.S., P.A.W., and H.Z. performed research; C.C.R., S.A.B., L.G.S., phenomenon of genetic toolkits challenges fundamental notions J.M.T., D.C.-A., and S.S. analyzed data; and C.C.R., S.S., G.E.R., and L.S. wrote the paper. about evolutionary convergence, conservation, and the origins of Reviewers: D.K., Columbia University; and K.P.W., The University of Chicago and Argonne biodiversity. National Laboratory. The role of genetic toolkits in shaping behavioral phenotypes is The authors declare no conflict of interest. unclear (4, 5). Behaviors are typically polygenic (6) and they show Freely available online through the PNAS open access option. great nuance and plasticity within a species, raising the possibility 1To whom correspondence may be addressed. Email: [email protected], generobi@illinois. that cross-species similarities in behavior are superficial. Social edu, or [email protected]. behaviors in particular present a challenge to the genetic toolkit 2S.A.B., L.G.S., and J.M.T. contributed equally to this work. concept: these behaviors are critical to survival and reproductive This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. success, but across species there is significant variation in the 1073/pnas.1420369111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1420369111 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 workers), which exhibits organized collective defensive behavior. associated with neural signaling and stimulus response. As This broad comparison enabled us to identify core molecular expected based on the brain regions assessed and the social context, mechanisms in the brain associated with the response to we found signatures of hormone signaling across all species. social challenge. For a subset of significant GO terms, we used post hoc analyses (Materials and Methods and SI Materials and Methods) to determine Results which genes were most responsible for enrichment of the term. For We sequenced mRNA to compare brain transcriptomes of ter- example, G-protein–coupled receptor (GPCR) activity was signifi- ritory holders exposed to either a conspecific intruder (experi- cantly enriched across all species and includes proteins integral to mental) or a neutral object (control). We sequenced different the response to hormones and neurotransmitters that modulate brain regions across the three species: honey bee whole brain behavior (12). Mouse GPCRs included a dopamine receptor [which shows a robust transcriptomic signature across multiple (Drd1a) and an adenosine receptor (Adora2a) associated with aggressive contexts (7)], stickleback diencephalon [which shows human panic disorders (13). Honey bee GPCRs included CcapR intense neural activation in response to intrusion (8)], and mouse and hormone receptor EthR, which are responsive to ecdysone ventral hypothalamus (VH) (9). We validated strong involvement (14, 15) (Table S1). Fz2,aWnt-activated receptor, was another of the VH, using brain regional quantitative PCR (qPCR) anal- GPCR identified in honey bee. Our GSEA results in mouse also ysis of several immediate early genes (IEGs) [Fos, Fosl2, Arc,and implicated Wnt signaling, suggesting a conserved role for this Egr1 (early growth response protein 1); Fig. S1]. Following se- classic developmental signaling pathway (16) in the response to quencing, we ranked all genes within a species based on the de- territory intrusion. gree of differential expression between experimental and control Our analyses also highlighted several other developmental pro- conditions and generated lists of significantly regulated Gene cesses, including
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