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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD022486-27
Application #
8737025
Study Section
Special Emphasis Panel (ZHD1-DSR-Y)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
27
Fiscal Year
2014
Total Cost
$349,321
Indirect Cost
$108,409
Name
University of Oregon
Department
Type
DUNS #
948117312
City
Eugene
State
OR
Country
United States
Zip Code
97403
Parthasarathy, Raghuveer (2017) Monitoring microbial communities using light sheet fluorescence microscopy. Curr Opin Microbiol 43:31-37
Sullivan, Con; Lage, Christopher R; Yoder, Jeffrey A et al. (2017) Evolutionary divergence of the vertebrate TNFAIP8 gene family: Applying the spotted gar orthology bridge to understand ohnolog loss in teleosts. PLoS One 12:e0179517
Melancon, E; Gomez De La Torre Canny, S; Sichel, S et al. (2017) Best practices for germ-free derivation and gnotobiotic zebrafish husbandry. Methods Cell Biol 138:61-100
Kroeger Jr, Paul T; Drummond, Bridgette E; Miceli, Rachel et al. (2017) The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development. Dev Biol 428:148-163
Yan, Yi-Lin; Desvignes, Thomas; Bremiller, Ruth et al. (2017) Gonadal soma controls ovarian follicle proliferation through Gsdf in zebrafish. Dev Dyn 246:925-945
Taormina, Michael J; Hay, Edouard A; Parthasarathy, Raghuveer (2017) Passive and Active Microrheology of the Intestinal Fluid of the Larval Zebrafish. Biophys J 113:957-965
Wangler, Michael F; Yamamoto, Shinya; Chao, Hsiao-Tuan et al. (2017) Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research. Genetics 207:9-27
Rolig, Annah S; Mittge, Erika K; Ganz, Julia et al. (2017) The enteric nervous system promotes intestinal health by constraining microbiota composition. PLoS Biol 15:e2000689
Blanco-Sánchez, B; Clément, A; Phillips, J B et al. (2017) Zebrafish models of human eye and inner ear diseases. Methods Cell Biol 138:415-467
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

Showing the most recent 10 out of 310 publications