Journal
NUCLEIC ACIDS RESEARCH
Volume 33, Issue 15, Pages 4914-4921Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gki799
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Funding
- NCI NIH HHS [R01 CA081008, R01 CA106633-02, R01 CA106633, R01 CA106633-04, CA81008, CA10663, R01 CA106633-01, R01 CA106633-03, N01 CO027175] Funding Source: Medline
- NIGMS NIH HHS [R01 GM063904, R01 GM063904-01] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA106633, R01CA081008] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM063904] Funding Source: NIH RePORTER
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During early zebrafish (Danio rerio) development zygotic transcription does not begin until the mid-blastula transition (MBT) similar to 3 h after fertilization. MBT demarcates transition from synchronous short cell cycles of S and M phases exclusively to full cycles encompassing G(1) and G(2) phases. Transcriptional profiling and RT-PCR analyses during these phases enabled us to determine that this shift corresponds to decreased transcript levels of S/M phase cell cycle control genes (e.g. ccna2, ccnb1, ccnb2 and ccne) and increased transcript levels of ccnd1, encoding cyclin D1, and orthologs of p21 (p21-like) and retinoblastoma (Rb-like 1). To investigate the regulation of this process further, the translation of ccnd1 mRNA, a G(1)/S checkpoint control element, was impaired by microinjection of ccnd1-specific morpholino phosphorodiamidate (MO) 20mer or hydroxyprolyl-phosphono peptide nucleic acid (HypNA-pPNA) 16mer antisense oligonucleotides. The resulting downregulation of cyclin D1 protein resulted in microophthalmia and microcephaly, but not lethality. The phenotypes were not seen with 3-mismatch MO 20mers or 1-mismatch HypNA-pPNA 16mers, and were rescued by an exogenous ccnd1 mRNA construct with five mismatches. Collectively, these results indicate that transcription of key molecular determinants of asynchronous cell cycle control in zebrafish embryos commences at MBT and that the reduction of cyclin D1 expression compromises zebrafish eye and head development.
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