title: Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice.
abstract: Neural tube defects (NTDs) are among the commonest and most severe forms of developmental defect, characterized by disruption of the early embryonic events of central nervous system formation. NTDs have long been known to exhibit a strong genetic dependence, yet the identity of the genetic determinants remains largely undiscovered. Initiation of neural tube closure is disrupted in mice homozygous for mutations in planar cell polarity (PCP) pathway genes, providing a strong link between NTDs and PCP signaling. Recently, missense gene variants have been identified in PCP genes in humans with NTDs, although the range of phenotypes is greater than in the mouse mutants. In addition, the sequence variants detected in affected humans are heterozygous, and can often be detected in unaffected individuals. It has been suggested that interactions between multiple heterozygous gene mutations cause the NTDs in humans. To determine the phenotypes produced in double heterozygotes, we bred mice with all three pairwise combinations of Vangl2(Lp), Scrib(Crc) and Celsr1(Crsh) mutations, the most intensively studied PCP mutants. The majority of double-mutant embryos had open NTDs, with the range of phenotypes including anencephaly and spina bifida, therefore reflecting the defects observed in humans. Strikingly, even on a uniform genetic background, variability in the penetrance and severity of the mutant phenotypes was observed between the different double-heterozygote combinations. Phenotypically, Celsr1(Crsh);Vangl2(Lp);Scrib(Crc) triply heterozygous mutants were no more severe than doubly heterozygous or singly homozygous mutants. We propose that some of the variation between double-mutant phenotypes could be attributed to the nature of the protein disruption in each allele: whereas Scrib(Crc) is a null mutant and produces no Scrib protein, Celsr1(Crsh) and Vangl2(Lp) homozygotes both express mutant proteins, consistent with dominant effects. The variable outcomes of these genetic interactions are of direct relevance to human patients and emphasize the importance of performing comprehensive genetic screens in humans.
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, TW20 0RD, UK. MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK. Jenny.Murdoch@rhul.ac.uk.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Murdoch
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Damrau
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK.
authors.forename: Anju
authors.initials: A
authors.lastname: Paudyal
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK.
authors.forename: Debora
authors.initials: D
authors.lastname: Bogani
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.affiliation: Newlife Birth Defects Research Centre, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Nicholas D E
authors.initials: ND
authors.lastname: Greene
authors.affiliation: Newlife Birth Defects Research Centre, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
authors.affiliation: Newlife Birth Defects Research Centre, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Copp
mesh_terms: D000483:Alleles; D000818:Animals; D016764:Cell Polarity / Q000235:genetics*; D006579:Heterozygote; D051379:Mice; D009154:Mutation; D009436:Neural Tube Defects / Q000235:genetics*
keywords: Craniorachischisis; Genetic interactions; Multiple heterozygosity; Neural tube defects; Planar cell polarity