Fraser syndrome (FS), an inherited birth defect, affects many tissues and organs and shows an outstanding level of variation in whether a genetically predisposed child will show FS symptoms, and if so, how severely the symptoms will be expressed and whether they are bilaterally symmetrical. An understanding of the molecular and cellular basis of this variation might lead to improved genetic counseling, diagnosis and treatment. FS can be caused by mutation of FRAS1 or related genes. FRASI protein is secreted by epithelial cells into the basal lamina, where it interacts with other proteins in a massive Fraser protein complex (FPC). The FPC, which likely functions in adhesion and signaling between the epithelium and underlying mesenchyme, is entirely disrupted in FS. Complexity in etiology, diagnosis, and treatment of FS and related birth defects is probably due to tissue-specific expression of FPC components and to stochastic variation in gene activities and cellular read-out. Nevertheless, all FS symptoms probably involve reduced and variable epithelial-mesenchymal interaction during development. Our mutational studies establish a zebrafish model of FS that we propose to exploit to learn about the causes of FS phenotypic variation. Zebrafish fras1 mutant phenotypes show themselves in the tail fin, and as this project exploits, in the head, where we examine variable disruptions in morphogenesis of both an epithelial pharyngeal pouch and the mesenchymal craniofacial skeleton - tissues homologous to those variably disrupted in human FS patients. We hypothesize that the FPC is a critical driver of pouch-mesenchyme interactions that normally buffers the effects of largely random perturbations of morphogenesis. We will use in vivo mosaic analyses, and time- lapse recordings at single cell-level resolution, to pinpoint tissue interactions, to learn how phenotypic variation relates to phenotypic severity of a mutation, and to discover when phenotypic variation increases in mutants. We will use a conditional fras1 allele to find the developmental period during which fras1* function is critical to reduce the high variation observed in the mutant. We will examine mutations in Fraser candidate genes to discover new components of the FPC, and we will provide high-resolution in vivo evidence for the proximity of FPC components and FPC stability in Fraser mutants. Further, we will use transcriptomics in an unbiased screen to identify genes and gene pathways downstream of FPC signaling, and hence to discover the mechanisms that erect the Fraser developmental buffering network.
Eraser syndrome Is a complex inherited birth defect affecting eyes, ears, kidneys and skin. It is difficult to diagnose and treat, at least in part because symptoms are highly variable, as in many inherited diseases. Proposed studies will examine Fraser syndrome variation in a zebrafish model, leading to a more complete understanding of the mechanisms whereby variation in embryonic development leads to variable clinical presentations in human disease, and paving the way toward better clinical diagnosis and treatment.
|Edmunds, Richard C; Su, Baofeng; Balhoff, James P et al. (2016) Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes. Mol Biol Evol 33:13-24|
|Burns, Adam R; Stephens, W Zac; Stagaman, Keaton et al. (2016) Contribution of neutral processes to the assembly of gut microbial communities in the zebrafish over host development. ISME J 10:655-64|
|Mason, Timothy; Snell, Kathy; Mittge, Erika et al. (2016) Strategies to Mitigate a Mycobacterium marinum Outbreak in a Zebrafish Research Facility. Zebrafish :|
|Wiles, Travis J; Jemielita, Matthew; Baker, Ryan P et al. (2016) Host Gut Motility Promotes Competitive Exclusion within a Model Intestinal Microbiota. PLoS Biol 14:e1002517|
|Hill, Jennifer Hampton; Franzosa, Eric A; Huttenhower, Curtis et al. (2016) A conserved bacterial protein induces pancreatic beta cell expansion during zebrafish development. Elife 5:|
|Zac Stephens, W; Burns, Adam R; Stagaman, Keaton et al. (2016) The composition of the zebrafish intestinal microbial community varies across development. ISME J 10:644-54|
|Talbot, Jared Coffin; Nichols, James T; Yan, Yi-Lin et al. (2016) Pharyngeal morphogenesis requires fras1-itga8-dependent epithelial-mesenchymal interaction. Dev Biol 416:136-48|
|Taylor, Charlotte R; Montagne, William A; Eisen, Judith S et al. (2016) Molecular fingerprinting delineates progenitor populations in the developing zebrafish enteric nervous system. Dev Dyn 245:1081-1096|
|Desvignes, Thomas; Detrich 3rd, H William; Postlethwait, John H (2016) Genomic conservation of erythropoietic microRNAs (erythromiRs) in white-blooded Antarctic icefish. Mar Genomics 30:27-34|
|Postlethwait, John H; Yan, Yi-Lin; Desvignes, Thomas et al. (2016) Embryogenesis and early skeletogenesis in the antarctic bullhead notothen, Notothenia coriiceps. Dev Dyn 245:1066-1080|
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