Multiple roles for the Na,K-ATPase subunits, Atp1a1 and Fxyd1, during brain ventricle development

Dev Biol. 2012 Aug 15;368(2):312-22. doi: 10.1016/j.ydbio.2012.05.034. Epub 2012 Jun 7.


Formation of the vertebrate brain ventricles requires both production of cerebrospinal fluid (CSF), and its retention in the ventricles. The Na,K-ATPase is required for brain ventricle development, and we show here that this protein complex impacts three associated processes. The first requires both the alpha subunit (Atp1a1) and the regulatory subunit, Fxyd1, and leads to formation of a cohesive neuroepithelium, with continuous apical junctions. The second process leads to modulation of neuroepithelial permeability, and requires Atp1a1, which increases permeability with partial loss of function and decreases it with overexpression. In contrast, fxyd1 overexpression does not alter neuroepithelial permeability, suggesting that its activity is limited to neuroepithelium formation. RhoA regulates both neuroepithelium formation and permeability, downstream of the Na,K-ATPase. A third process, likely to be CSF production, is RhoA-independent, requiring Atp1a1, but not Fxyd1. Consistent with a role for Na,K-ATPase pump function, the inhibitor ouabain prevents neuroepithelium formation, while intracellular Na(+) increases after Atp1a1 and Fxyd1 loss of function. These data include the first reported role for Fxyd1 in the developing brain, and indicate that the Na,K-ATPase regulates three aspects of brain ventricle development essential for normal function: formation of a cohesive neuroepithelium, restriction of neuroepithelial permeability, and production of CSF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Membrane Permeability
  • Cerebral Ventricles / drug effects
  • Cerebral Ventricles / embryology
  • Cerebral Ventricles / metabolism*
  • Cerebrospinal Fluid / metabolism
  • Embryo, Nonmammalian / drug effects
  • Embryo, Nonmammalian / embryology
  • Embryo, Nonmammalian / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Immunohistochemistry
  • In Situ Hybridization
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mutation
  • Neuroepithelial Cells / metabolism
  • Ouabain / pharmacology
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium / metabolism
  • Sodium-Potassium-Exchanging ATPase / genetics*
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish / metabolism
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism


  • Enzyme Inhibitors
  • Membrane Proteins
  • Phosphoproteins
  • Zebrafish Proteins
  • phospholemman
  • Ouabain
  • Sodium
  • atp1a1a.1 protein, zebrafish
  • rhoA GTP-Binding Protein
  • Sodium-Potassium-Exchanging ATPase