title: Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse.
abstract: Circletail is one of only two mouse mutants that exhibit the most severe form of neural tube defect (NTD), termed craniorachischisis. In this disorder, almost the entire brain and spinal cord is affected, owing to a failure to initiate neural tube closure. Craniorachischisis is a significant cause of lethality in humans, yet the molecular mechanisms involved remain poorly understood. Here, we report the identification of the gene mutated in circletail (Crc), using a positional cloning approach. This gene, Scrb1, encodes a member of the LAP protein family related to Drosophila scribble, with 16 leucine rich repeats and four PDZ domains. The Crc mutant contains a single base insertion that creates a frame shift and leads to premature termination of the Scrb1 protein. We report the expression pattern of Scrb1 during embryonic and fetal development, and show that Scrb1 expression closely mirrors the phenotypic defects observed in Crc/Crc mutants. In addition, circletail genetically interacts with the loop-tail mutant, and we reveal overlapping expression of Scrb1 with Vangl2, the gene mutated in loop-tail. The identification of the Crc gene further defines the nature of the genetic pathway required for the initiation of neural tube closure and provides an important new candidate that may be implicated in the aetiology of human NTDs.
authors.affiliation: Neural Development Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. j.murdoch@har.mrc.ac.uk
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Murdoch
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Henderson
authors.forename: Kit
authors.initials: K
authors.lastname: Doudney
authors.forename: Carles
authors.initials: C
authors.lastname: Gaston-Massuet
authors.forename: Helen M
authors.initials: HM
authors.lastname: Phillips
authors.forename: Caroline
authors.initials: C
authors.lastname: Paternotte
authors.forename: Ruth
authors.initials: R
authors.lastname: Arkell
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Copp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D005796:Genes / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D047908:Intracellular Signaling Peptides and Proteins
chemical_list: D008565:Membrane Proteins; C508433:scrib protein, mouse; D047908:Intracellular Signaling Peptides and Proteins