title: Mouse mutagenesis identifies novel roles for left-right patterning genes in pulmonary, craniofacial, ocular, and limb development.
abstract: 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.
authors.affiliation: Molecular Embryology Programme, MRC Mammalian Genetics Unit, Harwell, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ermakov
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Stevens
authors.forename: Elaine
authors.initials: E
authors.lastname: Whitehill
authors.forename: Joan E
authors.initials: JE
authors.lastname: Robson
authors.forename: Guido
authors.initials: G
authors.lastname: Pieles
authors.forename: Debra
authors.initials: D
authors.lastname: Brooker
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Goggolidou
authors.forename: Nicola
authors.initials: N
authors.lastname: Powles-Glover
authors.forename: Terry
authors.initials: T
authors.lastname: Hacker
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Young
authors.forename: Neil
authors.initials: N
authors.lastname: Dear
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hirst
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Tymowska-Lalanne
authors.forename: James
authors.initials: J
authors.lastname: Briscoe
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Norris
mesh_terms: 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