Mouse mutagenesis identifies novel roles for left-right patterning genes in pulmonary, craniofacial, ocular, and limb development.
Vertebrate organs show consistent left-right (L-R) asymmetry in placement and patterning. To identify genes involved in this process we performed an ENU-based genetic screen. Of 135 lines analyzed 11 showed clear single gene defects affecting L-R patterning, including 3 new alleles of known L-R genes and mutants in novel L-R loci. We identified six lines (termed "gasping") that, in addition to abnormal L-R patterning and associated cardiovascular defects, had complex phenotypes including pulmonary agenesis, exencephaly, polydactyly, ocular and craniofacial malformations. These complex abnormalities are present in certain human disease syndromes (e.g., HYLS, SRPS, VACTERL). Gasping embryos also show defects in ciliogenesis, suggesting a role for cilia in these human congenital malformation syndromes. Our results indicate that genes controlling ciliogenesis and left-right asymmetry have, in addition to their known roles in cardiac patterning, major and unexpected roles in pulmonary, craniofacial, ocular and limb development with implications for human congenital malformation syndromes.
Ermakov
Alexander
A
Molecular Embryology Programme, MRC Mammalian Genetics Unit, Harwell, United Kingdom.
Stevens
Jonathan L
JL
Whitehill
Elaine
E
Robson
Joan E
JE
Pieles
Guido
G
Brooker
Debra
D
Goggolidou
Paraskevi
P
Powles-Glover
Nicola
N
Hacker
Terry
T
Young
Stephen R
SR
Dear
Neil
N
Hirst
Elizabeth
E
Tymowska-Lalanne
Zuzanna
Z
Briscoe
James
J
Bhattacharya
Shoumo
S
Norris
Dominic P
DP
D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D005121:Extremities / Q000196:embryology*; D005123:Eye / Q000196:embryology* / Q000378:metabolism; D005147:Facial Bones / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D051379:Mice; D008855:Microscopy, Electron, Scanning; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012137:Respiratory System / Q000196:embryology* / Q000378:metabolism; D016415:Sequence Alignment