Dissecting spatio-temporal protein networks driving human heart development and related disorders.
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.
Lage
Kasper
K
Pediatric Surgical Research Laboratories, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, MA 02114, USA. lage.kasper@mgh.harvard.edu
Møllgård
Kjeld
K
Greenway
Steven
S
Wakimoto
Hiroko
H
Gorham
Joshua M
JM
Workman
Christopher T
CT
Bendsen
Eske
E
Hansen
Niclas T
NT
Rigina
Olga
O
Roque
Francisco S
FS
Wiese
Cornelia
C
Christoffels
Vincent M
VM
Roberts
Amy E
AE
Smoot
Leslie B
LB
Pu
William T
WT
Donahoe
Patricia K
PK
Tommerup
Niels
N
Brunak
Søren
S
Seidman
Christine E
CE
Seidman
Jonathan G
JG
Larsen
Lars A
LA
D002318:Cardiovascular Diseases / Q000196:embryology* / Q000378:metabolism*; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology*; D006801:Humans; D011506:Proteins / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction; D013997:Time Factors
D011506:Proteins