fras1 shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development.
Lesions in the epithelially expressed human gene FRAS1 cause Fraser syndrome, a complex disease with variable symptoms, including facial deformities and conductive hearing loss. The developmental basis of facial defects in Fraser syndrome has not been elucidated. Here we show that zebrafish fras1 mutants exhibit defects in facial epithelia and facial skeleton. Specifically, fras1 mutants fail to generate a late-forming portion of pharyngeal pouch 1 (termed late-p1) and skeletal elements adjacent to late-p1 are disrupted. Transplantation studies indicate that fras1 acts in endoderm to ensure normal morphology of both skeleton and endoderm, consistent with well-established epithelial expression of fras1. Late-p1 formation is concurrent with facial skeletal morphogenesis, and some skeletal defects in fras1 mutants arise during late-p1 morphogenesis, indicating a temporal connection between late-p1 and skeletal morphogenesis. Furthermore, fras1 mutants often show prominent second arch skeletal fusions through space occupied by late-p1 in wild type. Whereas every fras1 mutant shows defects in late-p1 formation, skeletal defects are less penetrant and often vary in severity, even between the left and right sides of the same individual. We interpret the fluctuating asymmetry in fras1 mutant skeleton and the changes in fras1 mutant skeletal defects through time as indicators that skeletal formation is destabilized. We propose a model wherein fras1 prompts late-p1 formation and thereby stabilizes skeletal formation during zebrafish facial development. Similar mechanisms of stochastic developmental instability might also account for the high phenotypic variation observed in human FRAS1 patients.
Institute of Neuroscience, University of Oregon, Eugene, OR 97403-1254, USA.
Jared Coffin
JC
Talbot
Macie B
MB
Walker
Thomas J
TJ
Carney
Tyler R
TR
Huycke
Yi-Lin
YL
Yan
Ruth A
RA
BreMiller
Linda
L
Gai
April
A
Delaurier
John H
JH
Postlethwait
Matthias
M
Hammerschmidt
Charles B
CB
Kimmel
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D003433:Crosses, Genetic; D004707:Endoderm / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000502:physiology*; D058497:Fraser Syndrome / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D012863:Skeleton; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
D016326:Extracellular Matrix Proteins; C575254:Fras1 protein, zebrafish; D029961:Zebrafish Proteins