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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.
Abbreviations
| BrdU | = | 5-Bromo-2′-deoxyuridine |
| CDK9 | = | cyclin-dependent kinase 9 |
| Fb | = | forebrain; mb – midbrain |
| hb | = | hindbrain |
| Mo | = | morpholino |
| P-TEFb | = | positive-acting transcription elongation factor |
| TUNEL | = | Terminal deoxynucleotidyl transferase dUTP nick end labeling |
| Ys | = | yolk sac |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Funding
This work was supported by the British Heart Foundation Centre of Research Excellence Award and the Medical Research Council (UK). G.M. was the recipient of a BHF PhD studentship.