title: Defective Nodal and Cerl2 expression in the Arl13b(hnn) mutant node underlie its heterotaxia.
abstract: Specification of the left-right axis during embryonic development is critical for the morphogenesis of asymmetric organs such as the heart, lungs, and stomach. The first known left-right asymmetry to occur in the mouse embryo is a leftward fluid flow in the node that is created by rotating cilia on the node surface. This flow is followed by asymmetric expression of Nodal and its inhibitor Cerl2 in the node. Defects in cilia and/or fluid flow in the node lead to defective Nodal and Cerl2 expression and therefore incorrect visceral organ situs. Here we show the cilia protein Arl13b is required for left right axis specification as its absence results in heterotaxia. We find the defect originates in the node where Cerl2 is not downregulated and asymmetric expression of Nodal is not maintained resulting in symmetric expression of both genes. Subsequently, Nodal expression is delayed in the lateral plate mesoderm (LPM). Symmetric Nodal and Cerl2 in the node could result from defects in either the generation and/ or the detection of Nodal flow, which would account for the subsequent defects in the LPM and organ positioning.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Larkins
authors.forename: Alyssa Bushey
authors.initials: AB
authors.lastname: Long
authors.forename: Tamara
authors.initials: T
authors.lastname: Caspary
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019521:Body Patterning; D004622:Embryo, Mammalian / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D055457:Nodal Protein / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000097577:Homeobox Protein PITX2
chemical_list: D020727:ADP-Ribosylation Factors; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055457:Nodal Protein; D011506:Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C560093:Arl13b protein, mouse; C119003:Dte protein, mouse; C526008:Nodal protein, mouse