Professor, Department of Biology
Ph.D. Brandeis University
B.S. Utah State
Research Interests: Specification and patterning of the vertebrate nervous system with a focus on developmental interactions between the nervous system, immune system, and host-associated microbiota
Overview: The vertebrate nervous system is composed of a large number of neurons with diverse characteristics that ultimately form the circuits that underlie an animal’s behavioral repertoire. We are interested in several aspects of this process including: 1) How neuronal diversity is generated during development: how are the correct number of cells specified for specific neural and glia fates at particular times and in particular locations? 2) How neuronal circuits are wired up: how do neurons make appropriate connections with their synaptic partners. 3) What are the roles of host-associated microbiota and the immune system during neural development: how do microbes associated with the host interact with the immune system and with the nervous system to shape neuronal architecture, circuitry, and function? We use an approach that combines cellular, molecular, genetic, and microbiological manipulations with live imaging in zebrafish to investigate these questions with the goal of understanding the mechanisms underlying neural development.
Evolution of Endothelin signaling and diversification of adult pigment pattern in Danio fishes.
PLoS Genet. 2018 09;14(9):e1007538
Authors: Spiewak JE, Bain EJ, Liu J, Kou K, Sturiale SL, Patterson LB, Diba P, Eisen JS, Braasch I, Ganz J, Parichy DM
Fishes of the genus Danio exhibit diverse pigment patterns that serve as useful models for understanding the genes and cell behaviors underlying the evolution of adult form. Among these species, zebrafish D. rerio exhibit several dark stripes of melanophores with sparse iridophores that alternate with light interstripes of dense iridophores and xanthophores. By contrast, the closely related species D. nigrofasciatus has an attenuated pattern with fewer melanophores, stripes and interstripes. Here we demonstrate species differences in iridophore development that presage the fully formed patterns. Using genetic and transgenic approaches we identify the secreted peptide Endothelin-3 (Edn3)-a known melanogenic factor of tetrapods-as contributing to reduced iridophore proliferation and fewer stripes and interstripes in D. nigrofasciatus. We further show the locus encoding this factor is expressed at lower levels in D. nigrofasciatus owing to cis-regulatory differences between species. Finally, we show that functions of two paralogous loci encoding Edn3 have been partitioned between skin and non-skin iridophores. Our findings reveal genetic and cellular mechanisms contributing to pattern differences between these species and suggest a model for evolutionary changes in Edn3 requirements for pigment patterning and its diversification across vertebrates.
PMID: 30226839 [PubMed - indexed for MEDLINE]
Forebrain Control of Behaviorally Driven Social Orienting in Zebrafish.
Curr Biol. 2018 Aug 06;28(15):2445-2451.e3
Authors: Stednitz SJ, McDermott EM, Ncube D, Tallafuss A, Eisen JS, Washbourne P
Deficits in social engagement are diagnostic of multiple neurodevelopmental disorders, including autism and schizophrenia . Genetically tractable animal models like zebrafish (Danio rerio) could provide valuable insight into developmental factors underlying these social impairments, but this approach is predicated on the ability to accurately and reliably quantify subtle behavioral changes. Similarly, characterizing local molecular and morphological phenotypes requires knowledge of the neuroanatomical correlates of social behavior. We leveraged behavioral and genetic tools in zebrafish to both refine our understanding of social behavior and identify brain regions important for driving it. We characterized visual social interactions between pairs of adult zebrafish and discovered that they perform a stereotyped orienting behavior that reflects social attention . Furthermore, in pairs of fish, the orienting behavior of one individual is the primary factor driving the same behavior in the other individual. We used manual and genetic lesions to investigate the forebrain contribution to this behavior and identified a population of neurons in the ventral telencephalon whose ablation suppresses social interactions, while sparing other locomotor and visual behaviors. These neurons are cholinergic and express the gene encoding the transcription factor Lhx8a, which is required for development of cholinergic neurons in the mouse forebrain . The neuronal population identified in zebrafish lies in a region homologous to mammalian forebrain regions implicated in social behavior such as the lateral septum . Our data suggest that an evolutionarily conserved population of neurons controls social orienting in zebrafish.
PMID: 30057306 [PubMed - in process]
Image velocimetry and spectral analysis enable quantitative characterization of larval zebrafish gut motility.
Neurogastroenterol Motil. 2018 Sep;30(9):e13351
Authors: Ganz J, Baker RP, Hamilton MK, Melancon E, Diba P, Eisen JS, Parthasarathy R
BACKGROUND: Normal gut function requires rhythmic and coordinated movements that are affected by developmental processes, physical and chemical stimuli, and many debilitating diseases. The imaging and characterization of gut motility, especially regarding periodic, propagative contractions driving material transport, are therefore critical goals. Previous image analysis approaches have successfully extracted properties related to the temporal frequency of motility modes, but robust measures of contraction magnitude, especially from in vivo image data, remain challenging to obtain.
METHODS: We developed a new image analysis method based on image velocimetry and spectral analysis that reveals temporal characteristics such as frequency and wave propagation speed, while also providing quantitative measures of the amplitude of gut motion.
KEY RESULTS: We validate this approach using several challenges to larval zebrafish, imaged with differential interference contrast microscopy. Both acetylcholine exposure and feeding increase frequency and amplitude of motility. Larvae lacking enteric nervous system gut innervation show the same average motility frequency, but reduced and less variable amplitude compared to wild types.
CONCLUSIONS & INFERENCES: Our image analysis approach enables insights into gut dynamics in a wide variety of developmental and physiological contexts and can also be extended to analyze other types of cell movements.
PMID: 29722095 [PubMed - in process]
Microbiota promote secretory cell determination in the intestinal epithelium by modulating host Notch signaling.
Development. 2018 02 23;145(4):
Authors: Troll JV, Hamilton MK, Abel ML, Ganz J, Bates JM, Stephens WZ, Melancon E, van der Vaart M, Meijer AH, Distel M, Eisen JS, Guillemin K
Resident microbes promote many aspects of host development, although the mechanisms by which microbiota influence host tissues remain unclear. We showed previously that the microbiota is required for allocation of appropriate numbers of secretory cells in the zebrafish intestinal epithelium. Because Notch signaling is crucial for secretory fate determination, we conducted epistasis experiments to establish whether the microbiota modulates host Notch signaling. We also investigated whether innate immune signaling transduces microbiota cues via the Myd88 adaptor protein. We provide the first evidence that microbiota-induced, Myd88-dependent signaling inhibits host Notch signaling in the intestinal epithelium, thereby promoting secretory cell fate determination. These results connect microbiota activity via innate immune signaling to the Notch pathway, which also plays crucial roles in intestinal homeostasis throughout life and when impaired can result in chronic inflammation and cancer.
PMID: 29475973 [PubMed - indexed for MEDLINE]
Guidelines for morpholino use in zebrafish.
PLoS Genet. 2017 10;13(10):e1007000
Authors: Stainier DYR, Raz E, Lawson ND, Ekker SC, Burdine RD, Eisen JS, Ingham PW, Schulte-Merker S, Yelon D, Weinstein BM, Mullins MC, Wilson SW, Ramakrishnan L, Amacher SL, Neuhauss SCF, Meng A, Mochizuki N, Panula P, Moens CB
PMID: 29049395 [PubMed - indexed for MEDLINE]
Correction: A MultiSite Gateway Toolkit for Rapid Cloning of Vertebrate Expression Constructs with Diverse Research Applications.
PLoS One. 2017;12(4):e0176543
Authors: Fowler DK, Stewart S, Seredick S, Eisen JS, Stankunas K, Washbourne P
[This corrects the article DOI: 10.1371/journal.pone.0159277.].
PMID: 28426753 [PubMed]
The enteric nervous system promotes intestinal health by constraining microbiota composition.
PLoS Biol. 2017 02;15(2):e2000689
Authors: Rolig AS, Mittge EK, Ganz J, Troll JV, Melancon E, Wiles TJ, Alligood K, Stephens WZ, Eisen JS, Guillemin K
Sustaining a balanced intestinal microbial community is critical for maintaining intestinal health and preventing chronic inflammation. The gut is a highly dynamic environment, subject to periodic waves of peristaltic activity. We hypothesized that this dynamic environment is a prerequisite for a balanced microbial community and that the enteric nervous system (ENS), a chief regulator of physiological processes within the gut, profoundly influences gut microbiota composition. We found that zebrafish lacking an ENS due to a mutation in the Hirschsprung disease gene, sox10, develop microbiota-dependent inflammation that is transmissible between hosts. Profiling microbial communities across a spectrum of inflammatory phenotypes revealed that increased levels of inflammation were linked to an overabundance of pro-inflammatory bacterial lineages and a lack of anti-inflammatory bacterial lineages. Moreover, either administering a representative anti-inflammatory strain or restoring ENS function corrected the pathology. Thus, we demonstrate that the ENS modulates gut microbiota community membership to maintain intestinal health.
PMID: 28207737 [PubMed - indexed for MEDLINE]
Best practices for germ-free derivation and gnotobiotic zebrafish husbandry.
Methods Cell Biol. 2017;138:61-100
Authors: Melancon E, Gomez De La Torre Canny S, Sichel S, Kelly M, Wiles TJ, Rawls JF, Eisen JS, Guillemin K
All animals are ecosystems with resident microbial communities, referred to as microbiota, which play profound roles in host development, physiology, and evolution. Enabled by new DNA sequencing technologies, there is a burgeoning interest in animal-microbiota interactions, but dissecting the specific impacts of microbes on their hosts is experimentally challenging. Gnotobiology, the study of biological systems in which all members are known, enables precise experimental analysis of the necessity and sufficiency of microbes in animal biology by deriving animals germ-free (GF) and inoculating them with defined microbial lineages. Mammalian host models have long dominated gnotobiology, but we have recently adapted gnotobiotic approaches to the zebrafish (Danio rerio), an important aquatic model. Zebrafish offer several experimental attributes that enable rapid, large-scale gnotobiotic experimentation with high replication rates and exquisite optical resolution. Here we describe detailed protocols for three procedures that form the foundation of zebrafish gnotobiology: derivation of GF embryos, microbial association of GF animals, and long-term, GF husbandry. Our aim is to provide sufficient guidance in zebrafish gnotobiotic methodology to expand and enrich this exciting field of research.
PMID: 28129860 [PubMed - indexed for MEDLINE]