Dissecting spatio-temporal protein networks driving human heart development and related disorders

Kasper Lage Hansen, Kjeld Mølgård, Steven Greenway, Hiroko Wakimoto, Joshua M. Gorham, Christopher Workman, Eske Bendsen, Niclas Tue Hansen, Olga Rigina, Francisco José Sousa Simões Almeida Roque, Cornelia Wiese, Vincent M. Christoffels, Amy E. Roberts, Leslie B. Smoot, William T. Pu, Patricia K. Donahoe, Niels Tommerup, Søren Brunak, Christine E. Seidman, Jonathan G. SeidmanLars A. Larsen

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    Abstract

    Aberrant organ development is associated with a wide spectrum of disorders, from schizophrenia to congenital heart disease, but systems-level insight into the underlying processes is very limited. Using heart morphogenesis as general model for dissecting the functional architecture of organ development, we combined detailed phenotype information from deleterious mutations in 255 genes with high-confidence experimental interactome data, and coupled the results to thorough experimental validation. Hereby, we made the first systematic analysis of spatio-temporal protein networks driving many stages of a developing organ identifying several novel signaling modules. Our results show that organ development relies on surprisingly few, extensively recycled, protein modules that integrate into complex higher-order networks. This design allows the formation of a complicated organ using simple building blocks, and suggests how mutations in the same genes can lead to diverse phenotypes. We observe a striking temporal correlation between organ complexity and the number of discrete functional modules coordinating morphogenesis. Our analysis elucidates the organization and composition of spatio-temporal protein networks that drive the formation of organs, which in the future may lay the foundation of novel approaches in treatments, diagnostics, and regenerative medicine.
    Original languageEnglish
    JournalMolecular Systems Biology
    Volume6
    Pages (from-to)381
    ISSN1744-4292
    DOIs
    Publication statusPublished - 2010

    Bibliographical note

    This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial Share Alike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.

    Keywords

    • genetics
    • polygenic common disorders
    • systems biology
    • organ developmental networks
    • proteomics

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