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Published on: August 25, 2019
Effects of Cyclin Dependent Kinase 9 inhibition on zebrafish larvae
Gianfranco Matrone1,2, John J Mullins1, Carl S Tucker1
1a British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh , Edinburgh , UK.
Abstract:
CDK9 is a known regulator of cellular transcription, growth and proliferation. Small molecule inhibitors are currently being developed and assessed in clinical trials as anti-cancer drugs. The zebrafish embryo provides an ideal model to explore the effects of CDK9 inhibition in-vivo. This has not been adequately explored previously at the level of a whole organism. We have compared and contrasted the effects of pharmacological and molecular inhibition of CDK9 on somatic growth, apoptosis and cellular proliferation in zebrafish larvae between 0 to 120 hours post fertilisation (hpf) using flavopiridol, a selective CDK9 antagonist, and CDK9-targeting morpholino. We demonstrate that the inhibition of CDK9 diminishes cellular proliferation and increases apoptosis. Subsequently, it affects somatic growth and development of a number of key embryonic structures including the brain, heart, eye and blood vessels. For the first time, we have localized CDK9 at a subcellular level in whole-mounted larvae. This works shows, at a high-throughput level, that CDK9 clearly plays a fundamental role in early cellular growth and proliferation.
Insights
Cyclin-dependent kinase 9 (CDK9) inhibition in zebrafish embryos reduces cell proliferation and increases apoptosis, impacting embryonic development. This study highlights CDK9
Area of Science:
- Molecular Biology
- Developmental Biology
- Pharmacology
Background:
- Cyclin-dependent kinase 9 (CDK9) is a key regulator of transcription, growth, and proliferation.
- CDK9 inhibitors are being investigated as anti-cancer therapeutics.
- In vivo studies of CDK9 inhibition in whole organisms, like zebrafish, are limited.
Purpose of the Study:
- To investigate the in vivo effects of CDK9 inhibition on zebrafish embryonic development.
- To compare pharmacological and molecular inhibition of CDK9.
- To localize CDK9 within larval tissues.
Main Methods:
- Pharmacological inhibition using flavopiridol (a selective CDK9 antagonist).
- Molecular inhibition using CDK9-targeting morpholino.
- Assessment of somatic growth, apoptosis, and cellular proliferation in zebrafish larvae (0-120 hours post-fertilization).
- Subcellular localization of CDK9 in whole-mounted larvae.
Main Results:
- CDK9 inhibition significantly reduced cellular proliferation.
- CDK9 inhibition led to increased apoptosis.
- Inhibition impacted somatic growth and the development of critical embryonic structures (brain, heart, eye, blood vessels).
Conclusions:
- CDK9 plays a fundamental role in early cellular growth and proliferation.
- Zebrafish embryos are a suitable model for high-throughput in vivo studies of CDK9 function.
- CDK9 inhibition has significant consequences for embryonic development.
