Open AccessDissecting spatio‐temporal protein networks driving human heart development and related disorders
Author(s) -
Lage Kasper,
Møllgård Kjeld,
Greenway Steven,
Wakimoto Hiroko,
Gorham Joshua M,
Workman Christopher T,
Bendsen Eske,
Hansen Niclas T,
Rigina Olga,
Roque Francisco S,
Wiese Cornelia,
Christoffels Vincent M,
Roberts Amy E,
Smoot Leslie B,
Pu William T,
Donahoe Patricia K,
Tommerup Niels,
Brunak Søren,
Seidman Christine E,
Seidman Jonathan G,
Larsen Lars A
Publication year - 2010
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb.2010.36
Subject(s) - interactome , biology , morphogenesis , computational biology , phenotype , gene regulatory network , systems biology , clinical phenotype , bioinformatics , gene , neuroscience , genetics , gene expression
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.