Abstract
Cell proliferation has generally been considered dispensable for anteroposterior extension of embryonic axis during vertebrate gastrulation. Signal transducer and activator of transcription 3 (Stat3), a conserved controller of cell proliferation, survival and regeneration, is associated with human scoliosis, cancer and Hyper IgE Syndrome. Zebrafish Stat3 was proposed to govern convergence and extension gastrulation movements in part by promoting Wnt/Planar Cell Polarity (PCP) signaling, a conserved regulator of mediolaterally polarized cell behaviors. Here, using zebrafish stat3 null mutants and pharmacological tools, we demonstrate that cell proliferation contributes to anteroposterior embryonic axis extension. Zebrafish embryos lacking maternal and zygotic Stat3 expression exhibit normal convergence movements and planar cell polarity signaling, but transient axis elongation defect due to insufficient number of cells resulting largely from reduced cell proliferation and increased apoptosis. Pharmacologic inhibition of cell proliferation during gastrulation phenocopied axis elongation defects. Stat3 regulates cell proliferation and axis extension in part via upregulation of Cdc25a expression during oogenesis. Accordingly, restoring Cdc25a expression in stat3 mutants partially suppressed cell proliferation and gastrulation defects. During later development, stat3 mutant zebrafish exhibit stunted growth, scoliosis, excessive inflammation, and fail to thrive, affording a genetic tool to study Stat3 function in vertebrate development, regeneration, and disease.
Highlights
Signal transducer and activator of transcription 3 (STAT3) is an essential mediator of cytokine and growth factor signaling involved in animal development, homeostasis and disease [1, 2]
We report that zebrafish mutants lacking maternal and zygotic Signal transducer and activator of transcription 3 (Stat3) expression exhibit normal convergence movements and planar cell polarity signaling, but transient axis elongation defect due to insufficient number of cells resulting largely from reduced cell proliferation and increased cell death
Further experiments indicate that Stat3 promotes head- to -tail axis elongation by stimulating cell proliferation in part via upregulation of Cdc25a expression during oogenesis
Summary
Signal transducer and activator of transcription 3 (STAT3) is an essential mediator of cytokine and growth factor signaling involved in animal development, homeostasis and disease [1, 2]. STAT3 activates or inhibits expression of downstream genes involved in cell proliferation, apoptosis, stem cell maintenance, differentiation, and migration in normal tissues. Non-transcriptional functions of STAT3 in microtubule, mitochondria, and chromatin regulation have been reported [3, 4]. Constitutively active STAT3 drives cell proliferation through upregulation of cell cycle-regulators such as c-Myc and Cyclin D, promotes pluripotency of cancer stem cells, and potentiates metastasis by modulating cytoskeleton and extracellular matrix [4, 5]. Disruption of murine Stat in hematopoietic cells causes Crohn’s disease-like immunodeficiency [9]
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