Novel regulator of Notch signaling in determination of left-right asymmetry durin

Florida State University, Tallahassee FL

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Abstract

DESCRIPTION (provided by applicant): SUMMARY: Despite the external bilateral symmetry of human body, there are many interior left-right (LR) asymmetries within the disposition and placement of internal organs. A failure of LR asymmetry determination during embryogenesis leads to inverted position of internal organs named heterotaxia. Importantly, over 80 % of children with situs ambiguous, an anatomical derangement triggered by the defect of LR asymmetry determination, present with complications of congenital heart disease including transposition of the great arteries, double outlet right ventricle, double inlet left ventricle, atrioventricular septal defects and total anomalous pulmonary venous connection. The determination of LR asymmetry has been shown to be regulated by various molecules and signal transduction pathways including the Notch signaling pathway. This pathway is an evolutionally conserved pathway that is involved in many aspects of development and human diseases. While Notch signaling mediates local cell-cell communication and regulates downstream responses including cell-fate specification, progenitor cell maintenance, boundary formation, cell proliferation and apoptosis, the molecular mechanisms of how Notch signaling governs LR asymmetry determination are not completely clear. Recently we have isolated the B-cell leukemia/lymphoma 6 (BCL6), a transcriptional repressor, as a novel Notch-associated factor by immunoprecipitation approach combined with proteomics analysis. Our studies show that Notch signaling can suppress the expression of Pitx2, a left-specific gene, on the left lateral plate mesoderm and BCL6 inhibits its activity to maintain LR asymmetry. For this, BCL6 interferes with the interaction between Notch and Mastermind-like1, a co-activator, in the transcriptional complex of Notch signaling. However, Notch-downstream genes suppressed by BCL6 have not been identified and how these molecules affect the determination of LR asymmetry still remains unsolved. In this proposal, we will address these two important questions by using techniques of molecular biology and developmental biology including whole mount in situ hybridization, chromatin immunoprecipitation and gain-of-function and loss-of-function studies in Xenopus embryos. Our studies will uncover new mechanisms and insights into how Notch signaling regulates LR asymmetry and deepen our understanding of how the deregulation of this pathway leads to human congenital diseases. PUBLIC HEALTH RELEVANCE: NARRATIVE: The Notch signaling pathway has been shown to play crucial roles in many biological processes and the deregulation of this signaling pathway has been identified in human diseases including congenital diseases and cancers. Progresses in the identification and the characterization of novel factors, which regulates this pathway, will lead to the identification of numerous genes that are responsible for human diseases.