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Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates
Dany S. Adams1,
Kenneth R. Robinson2,
Takahiro Fukumoto3,*,
Shipeng Yuan4,
R. Craig Albertson3,
Pamela Yelick3,
Lindsay Kuo3,
Megan McSweeney3, and
Michael Levin1,
1 The Forsyth Center for Regenerative and Developmental Biology, and Department
of Developmental Biology, Harvard School of Dental Medicine, 140 The Fenway,
Boston, MA 02115, USA. 2 Department of Biological Sciences, Purdue University, West Lafayette, IN
47906, USA. 3 Department of Cytokine Biology, The Forsyth Institute, 140 The Fenway, Boston,
MA 02115, USA. 4 Cardiovascular Research Center, Massachusetts General Hospital, Harvard
Medical School, Charlestown, MA 02129, USA.
Author for correspondence (e-mail:
mlevin{at}forsyth.org)
Accepted for publication 27 February 2006.
Abstract:
Biased left-right asymmetry is a fascinating and medically important
phenomenon.We provide molecular genetic and physiological characterizationof
a novel, conserved, early, biophysical event that is crucialfor correct
asymmetry: H+ flux. A pharmacological screen implicatedthe
H+-pump H+-V-ATPase in Xenopus asymmetry, where
it actsupstream of early asymmetric markers. Immunohistochemistry revealedan
actin-dependent asymmetry of H+-V-ATPase subunits duringthe first
three cleavages. H+-flux across plasma membranes isalso asymmetric
at the four- and eight-cell stages, and thisasymmetry requires
H+-V-ATPase activity. Abolishing the asymmetryin H+
flux, using a dominant-negative subunit of the H+-V-ATPaseor an
ectopic H+ pump, randomized embryonic situs without causingany
other defects. To understand the mechanism of action of
H+-V-ATPase,we isolated its two physiological functions,
cytoplasmic pHand membrane voltage (Vmem) regulation. Varying
either pH orVmem, independently of direct manipulation of
H+-V-ATPase, causeddisruptions of normal asymmetry, suggesting
roles for both functions.V-ATPase inhibition also abolished the normal early
localizationof serotonin, functionally linking these two early asymmetry
pathways.The involvement of H+-V-ATPase in asymmetry is conserved
tochick and zebrafish. Inhibition of the H+-V-ATPase induces
heterotaxiain both species; in chick, H+-V-ATPase activity is
upstreamof Shh; in fish, it is upstream of Kupffer's vesicle and
Spawexpression. Our data implicate H+-V-ATPase activity
in patterningthe LR axis of vertebrates and reveal mechanisms upstream and
downstreamof its activity. We propose a pH- and Vmem-dependent
model ofthe early physiology of LR patterning.
Identification of Domains within the V-ATPase Accessory Subunit Ac45 Involved in V-ATPase Transport and Ca2+-dependent Exocytosis.
E. J. R. Jansen, N. H. M. van Bakel, N. F. M. O. Loohuis, T. G. M. Hafmans, T. Arentsen, A. J. M. Coenen, W. J. J. M. Scheenen, and G. J. M. Martens (2012)
J. Biol. Chem.
287, 27537-27546
|Abstract »|Full Text »|PDF »
Early, nonciliary role for microtubule proteins in left-right patterning is conserved across kingdoms.
M. Lobikin, G. Wang, J. Xu, Y.-W. Hsieh, C.-F. Chuang, J. M. Lemire, and M. Levin (2012)
PNAS
109, 12586-12591
|Abstract »|Full Text »|PDF »
The reconstructed ancestral subunit a functions as both V-ATPase isoforms Vph1p and Stv1p in Saccharomyces cerevisiae.
G. C. Finnigan, V. Hanson-Smith, B. D. Houser, H. J. Park, and T. H. Stevens (2011)
Mol. Biol. Cell
22, 3176-3191
|Abstract »|Full Text »|PDF »
L. Q. Wan, K. Ronaldson, M. Park, G. Taylor, Y. Zhang, J. M. Gimble, and G. Vunjak-Novakovic (2011)
PNAS
108, 12295-12300
|Abstract »|Full Text »|PDF »
Transmembrane potential of GlyCl-expressing instructor cells induces a neoplastic-like conversion of melanocytes via a serotonergic pathway.
D. Blackiston, D. S. Adams, J. M. Lemire, M. Lobikin, and M. Levin (2011)
Dis. Model. Mech.
4, 67-85
|Abstract »|Full Text »|PDF »
V-ATPase-Mediated Granular Acidification Is Regulated by the V-ATPase Accessory Subunit Ac45 in POMC-Producing Cells.
E. J. R. Jansen, T. G. M. Hafmans, and G. J. M. Martens (2010)
Mol. Biol. Cell
21, 3330-3339
|Abstract »|Full Text »|PDF »
Consistent left-right asymmetry cannot be established by late organizers in Xenopus unless the late organizer is a conjoined twin.
Calcium dynamics integrated into signalling pathways that influence vertebrate axial patterning.
C. M Freisinger, I. Schneider, T. A Westfall, and D. C Slusarski (2008)
Phil Trans R Soc B
363, 1377-1385
|Abstract »|Full Text »|PDF »
Biochemical and functional characterization of the actin-binding activity of the B subunit of yeast vacuolar H+-ATPase.
J. Zuo, S. Vergara, S. Kohno, and L. S. Holliday (2008)
J. Exp. Biol.
211, 1102-1108
|Abstract »|Full Text »|PDF »
Exclusion of a Proton ATPase from the Apical Membrane Is Associated with Cell Polarity and Tip Growth in Nicotiana tabacum Pollen Tubes.
A. C. Certal, R. B. Almeida, L. M. Carvalho, E. Wong, N. Moreno, E. Michard, J. Carneiro, J. Rodriguez-Leon, H.-M. Wu, A. Y. Cheung, et al. (2008)
PLANT CELL
20, 614-634
|Abstract »|Full Text »|PDF »
Calcium fluxes in dorsal forerunner cells antagonize -catenin and alter left-right patterning.
I. Schneider, D. W. Houston, M. R. Rebagliati, and D. C. Slusarski (2008)
Development
135, 75-84
|Abstract »|Full Text »|PDF »
Na,K-ATPase {alpha}2 and Ncx4a regulate zebrafish left-right patterning.
X. Shu, J. Huang, Y. Dong, J. Choi, A. Langenbacher, and J.-N. Chen (2007)
Development
134, 1921-1930
|Abstract »|Full Text »|PDF »
H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induce Xenopus tail regeneration.
