Coordinated Regulation of Signaling Pathways and Biological Processes during Liver Development

Understanding congenital liver disease requires elucidation of the signaling pathways and transcriptional events in the developing liver. Comprehensive assessment of gene expression between 10.5 and 16.5 dpc in the developing mouse liver and comparison with adult liver and non-hepatic embryonic tissue was validated with real-time PCR and in situ hybridization. The broad nature of the analysis provides insights into patterns of genetic control of hepatogenesis. Pathways implicated in human disease are highly regulated at the transcriptional level. Rather than activating or inhibiting a pathway or biological process by altering the expression of a single signaling molecule, transcriptional changes in large numbers of genes in a pathway or process are regulated in a coordinated manner. For example, both TGF-beta and Notch signaling is inhibited during hepatogenesis not just by decreasing transcription of multiple pathway members, but also with a complementary increase in the transcription of a pathway inhibitor. Similarly, genes related to specific biological processes exhibit strong temporal synchronization in which multiple members of the pathway have similar transcriptional regulation over time. Global coordination of signaling or functional families at the transcriptional level may be a mechanism to produce robustness of the desired outcomes. In addition, this comprehensive analysis provides a database for the further study of transcriptional events during liver development by identifying liver-specific, highly regulated genes.

18