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    Regulation of the FGF/ERK Signaling Pathway: Roles in Zebrafish Gametogenesis and Embryogenesis

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    Authors
    Maurer, Jennifer M.
    Faculty Advisor
    Charles G. Sagerstrom
    Academic Program
    Biochemistry and Molecular Pharmacology
    UMass Chan Affiliations
    Biochemistry and Molecular Pharmacology
    Document Type
    Doctoral Dissertation
    Publication Date
    2017-10-13
    Keywords
    CRISPR
    ERK signaling
    dual-specific phosphatase
    MAP kinase phosphatase
    germ cell development
    zebrafish embryonic patterning
    Biochemistry
    Developmental Biology
    Developmental Neuroscience
    Molecular Biology
    Molecular Genetics
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    Abstract
    Signaling cascades, such as the extracellular signal-regulated kinase (ERK) pathway, play vital roles in early vertebrate development. Signals through these pathways are initiated by a growth factor or hormone, are transduced through a kinase cascade, and result in the expression of specific downstream genes that promote cellular proliferation, growth, or differentiation. Tight regulation of these signals is provided by positive or negative modulators at varying levels in the pathway, and is required for proper development and function. Two members of the dual-specificity phosphatase (Dusp) family, dusp6 and dusp2, are believed to be negative regulators of the ERK pathway and are expressed in both embryonic and adult zebrafish, but their specific roles in gametogenesis and embryogenesis remain to be fully understood. Using CRISPR/Cas9 genome editing technology, we generated zebrafish lines harboring germ line deletions in dusp6 and dusp2. We do not detect any overt defects in dusp2 mutants, but we find that approximately 50% of offspring from homozygous dusp6 mutants do not proceed through embryonic development. These embryos are fertilized, but are unable to proceed past the first zygotic mitosis and stall at the one-cell stage for several hours before dying by 10 hours post fertilization. We demonstrate that dusp6 is expressed in the gonads of both male and female zebrafish, suggesting that loss of dusp6 causes defects in germ cell production. Notably, the 50% of homozygous dusp6 mutants that complete the first cell division appear to progress through embryogenesis normally and give rise to fertile adults. The fact that offspring of homozygous dusp6 mutants stall at the one-cell stage, prior to activation of the zygotic genome, suggests that loss of dusp6 affects gametogenesis. Further, since only approximately 50% of homozygous dusp6 mutants are affected, we postulate that ERK signaling is tightly regulated and that dusp6 is required to keep ERK signaling within a range that is permissive for gametogenesis. Lastly, since dusp6 is expressed throughout zebrafish embryogenesis, but dusp6 mutants do not exhibit defects after the first cell division, it is possible that other feedback regulators of the ERK pathway compensate for loss of dusp6 at later stages.
    DOI
    10.13028/M2ZD5V
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32308
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M2ZD5V
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