Abstract
Tendons and ligaments are crucial components of the musculoskeletal system, yet the pathways specifying these fates remain poorly defined. Through a screen of known bioactive chemicals in zebrafish, we identified a new pathway regulating tendon cell induction. We established that statin, through inhibition of the mevalonate pathway, causes an expansion of the tendon progenitor population. Co-expression and live imaging studies indicate that the expansion does not involve an increase in cell proliferation, but rather results from re-specification of cells from the neural crest-derived sox9a+/sox10+ skeletal lineage. The effect on tendon cell expansion is specific to the geranylgeranylation branch of the mevalonate pathway and is mediated by inhibition of Rac activity. This work establishes a novel role for the mevalonate pathway and Rac activity in regulating specification of the tendon lineage.
Keywords:
Chemical screen; Scleraxis; Statin; Tendon; Zebrafish.
© 2020. Published by The Company of Biologists Ltd.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors
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Alkyl and Aryl Transferases / genetics
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Alkyl and Aryl Transferases / metabolism
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Animals
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Animals, Genetically Modified / metabolism
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Atorvastatin / pharmacology
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects
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Farnesyltranstransferase / antagonists & inhibitors
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Farnesyltranstransferase / genetics
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Farnesyltranstransferase / metabolism
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Mevalonic Acid / metabolism*
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Morpholinos / metabolism
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Neural Crest / metabolism
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SOX9 Transcription Factor / genetics
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SOX9 Transcription Factor / metabolism
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SOXE Transcription Factors / genetics
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SOXE Transcription Factors / metabolism
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Signal Transduction
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Stem Cells / cytology
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Stem Cells / metabolism
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Tendons / cytology
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Tendons / metabolism*
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Tendons / pathology
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Zebrafish / metabolism
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Zebrafish Proteins / antagonists & inhibitors
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism
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rac GTP-Binding Proteins / antagonists & inhibitors
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rac GTP-Binding Proteins / metabolism
Substances
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Morpholinos
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SOX9 Transcription Factor
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SOXE Transcription Factors
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Sox9a protein, zebrafish
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Zebrafish Proteins
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sox10 protein, zebrafish
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Atorvastatin
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Alkyl and Aryl Transferases
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geranylgeranyltransferase type-I
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Farnesyltranstransferase
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rac GTP-Binding Proteins
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Mevalonic Acid