TY - JOUR

T1 - Dissecting spatio-temporal protein networks driving human heart development and related disorders

AU - Hansen, Kasper Lage

AU - Møllgård, Kjeld

AU - Greenway, Steven

AU - Wakimoto, Hiroko

AU - Gorham, Joshua M

AU - Workman, Christopher T

AU - Bendsen, Eske

AU - Hansen, Niclas T

AU - Rigina, Olga

AU - Roque, Francisco S

AU - Wiese, Cornelia

AU - Christoffels, Vincent M

AU - Roberts, Amy E

AU - Smoot, Leslie B

AU - Pu, William T

AU - Donahoe, Patricia K

AU - Tommerup, Niels

AU - Brunak, Søren

AU - Seidman, Christine E

AU - Seidman, Jonathan G

AU - Larsen, Lars A

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1038/msb.2010.36

DO - 10.1038/msb.2010.36

M3 - Journal article

C2 - 20571530

VL - 6

SP - 381

JO - Molecular Systems Biology

JF - Molecular Systems Biology

SN - 1744-4292

ER -