PUBLICATION
Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates
- Authors
- Adams, D.S., Robinson, K.R., Fukumoto, T., Yuan, S., Albertson, R.C., Yelick, P., Kuo, L., McSweeney, M., and Levin, M.
- ID
- ZDB-PUB-060327-4
- Date
- 2006
- Source
- Development (Cambridge, England) 133(9): 1657-1671 (Journal)
- Registered Authors
- Albertson, R. Craig, Yelick, Pamela C., Yuan, Shipeng
- Keywords
- Left-right asymmetry, H+-V-ATPase, V-ATPase, Xenopus, Chick, Zebrafish, Axial patterning, Cytoplasmic pH, Membrane voltage
- MeSH Terms
-
- Actins/metabolism
- Embryo, Nonmammalian
- Animals
- Proton Pump Inhibitors
- Zebrafish/embryology
- Models, Biological
- Enzyme Inhibitors/pharmacology
- Gene Expression Regulation, Developmental
- Chick Embryo
- Cell Membrane/metabolism
- Vertebrates/embryology*
- Body Patterning*
- Xenopus/embryology
- Immunohistochemistry
- Protons*
- Hydrogen-Ion Concentration
- H(+)-K(+)-Exchanging ATPase/chemistry*
- H(+)-K(+)-Exchanging ATPase/metabolism*
- Time Factors
- PubMed
- 16554361 Full text @ Development
Citation
Adams, D.S., Robinson, K.R., Fukumoto, T., Yuan, S., Albertson, R.C., Yelick, P., Kuo, L., McSweeney, M., and Levin, M. (2006) Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates. Development (Cambridge, England). 133(9):1657-1671.
Abstract
Biased left-right asymmetry is a fascinating and medically important phenomenon. We provide molecular genetic and physiological characterization of a novel, conserved, early, biophysical event that is crucial for correct asymmetry: H(+) flux. A pharmacological screen implicated the H(+)-pump H(+)-V-ATPase in Xenopus asymmetry, where it acts upstream of early asymmetric markers. Immunohistochemistry revealed an actin-dependent asymmetry of H(+)-V-ATPase subunits during the first three cleavages. H(+)-flux across plasma membranes is also asymmetric at the four- and eight-cell stages, and this asymmetry requires H(+)-V-ATPase activity. Abolishing the asymmetry in H(+) flux, using a dominant-negative subunit of the H(+)-V-ATPase or an ectopic H(+) pump, randomized embryonic situs without causing any other defects. To understand the mechanism of action of H(+)-V-ATPase, we isolated its two physiological functions, cytoplasmic pH and membrane voltage (Vmem) regulation. Varying either pH or Vmem, independently of direct manipulation of H(+)-V-ATPase, caused disruptions of normal asymmetry, suggesting roles for both functions. V-ATPase inhibition also abolished the normal early localization of serotonin, functionally linking these two early asymmetry pathways. The involvement of H(+)-V-ATPase in asymmetry is conserved to chick and zebrafish. Inhibition of the H(+)-V-ATPase induces heterotaxia in both species; in chick, H(+)-V-ATPase activity is upstream of Shh; in fish, it is upstream of Kupffer's vesicle and Spaw expression. Our data implicate H(+)-V-ATPase activity in patterning the LR axis of vertebrates and reveal mechanisms upstream and downstream of its activity. We propose a pH- and Vmem-dependent model of the early physiology of LR patterning.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping