| Popis: |
The digestive system is derived from the endoderm, consisting of the alimentary canal and its associated organs: liver, gall bladder and pancreas. Despite the essential functions of the liver, comparatively little is known about the molecular network controlling liver formation. In a forward genetic screen for factors involved in endodermal organogenesis, the clampeds819 mutant has been identified and displays defects in liver size. Positional cloning has mapped the molecular lesion underlying the clampeds819 mutant phenotype to structure specific recognition protein 1a (ssrp1a). Ssrp1 is a component of the FACT (facilitates chromatin transcription) hetero-dimer. Ssrp1 regulates nucleosome stability by interacting with histones H4 and H3 and is required for DNA synthesis and transcription. Phenotypic analysis of ssrp1as819 mutants revealed that liver specification is unperturbed, while subsequent differentiation and growth are disrupted. Analysis of liver proliferation uncovered defects in hepatic cell cycle progression, namely hepatoblast arrest in S-phase in ssrp1as819 mutants. These proliferation defects are followed by cell death, which in ssrp1as819 mutants is only partially p53 dependent. Analysis of RNA synthesis showed that Ssrp1a is required for gene transcription, revealing potential differences in mRNA stability between various transcripts, as some cell cycle regulators are absent and p53 target genes appear to exhibit more stable transcripts. Similar defects have been determined during eye organogenesis in the absence of Ssrp1a, suggesting that Ssrp1a is generally required during later stages of development in highly proliferative tissues. Furthermore, the late onset of the ssrp1as819 mutant phenotype is likely due to maternal Ssrp1a or other redundant factors such as Ssrp1b. Altogether, these data for the first time show a requirement for zygotic Ssrp1a in cell cycle progression within the liver and eye, and demonstrate its critical role during specific phases of organ growth and differentiation. |
