title: Lmbrd1 expression is essential for the initiation of gastrulation.
abstract: The rare inborn cblF defect of cobalamin metabolism is caused by mutations in the limb region 1 (LMBR1) domain containing 1 gene (LMBRD1). This defect is characterized by massive accumulation of free cobalamin in lysosomes and loss of mitochondrial succinyl-CoA synthesis and cytosolic methionine synthesis. Affected children suffer from heart defects, developmental delay and megaloblastic anemia. LMBRD1 encodes for LMBD1, a predicted lysosomal cobalamin transport protein. In this study, we determine the physiological function of LMBRD1 during embryogenesis by generating Lmbrd1 deficient mice using the Cre/LoxP system. Complete loss of Lmbrd1 function is accompanied by early embryonic death in mice. Whole mount in situ hybridization studies against bone morphogenetic protein 4 and Nodal show that initial formation of the proximal-distal axis is unaffected in early embryonic stages whereas the initiation of gastrulation is disturbed shown by the expression pattern of even skipped homeotic gene 1 and fibroblast growth factor 8 in Lmbrd1 deficient mice. We conclude that intact function of LMBD1 is essential for the initiation of gastrulation.
authors.affiliation: Department of General Pediatrics, Müenster University Children's Hospital, Müenster, Germany.
authors.forename: Insa
authors.initials: I
authors.lastname: Buers
authors.affiliation: Department of General Pediatrics, Müenster University Children's Hospital, Müenster, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Pennekamp
authors.affiliation: Department of General Pediatrics, Müenster University Children's Hospital, Müenster, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nitschke
authors.affiliation: Department of General Pediatrics, Müenster University Children's Hospital, Müenster, Germany.
authors.forename: Chrishanthi
authors.initials: C
authors.lastname: Lowe
authors.affiliation: Institute of Experimental Pathology, Müenster University, Müenster, Germany.|Department of Medicine (TRAM), University Hospital of Müenster, Münster, Germany.
authors.forename: Boris V
authors.initials: BV
authors.lastname: Skryabin
authors.affiliation: Department of General Pediatrics, Müenster University Children's Hospital, Müenster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005260:Female; D054262:Gastrulation; D018390:Gene Targeting; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism*; D014162:Transfection
chemical_list: D015415:Biomarkers; C496503:Foxa2 protein, mouse; C000621080:Lmbrd1 protein, mouse; D029543:Nucleocytoplasmic Transport Proteins; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: Lmbrd1−/−-embryos; cobalamin metabolism; embryonic development; gastrulation