The first evident break in left-right symmetry of the primitive zebrafish heart tube is the shift in pattern of BMP4 expression from radially symmetric to left-predominant. The midline heart tube then ‘jogs’ to the left and subsequently loops to the right. We examined 279 mutations, affecting more than 200 genes, and found 21 mutations that perturb this process. Some cause BMP4 to remain radially symmetric. Others randomize the asymmetric BMP4 pattern. Retention of BMP4 symmetry is associated with failure to jog: right-predominance of the BMP4 pattern is associated with reversal of the direction of jogging and looping. Raising BMP4 diffusely throughout the heart, via sonic hedgehog injection, or the blocking of its action by injection of a dominant negative BMP4 receptor, prevent directional jogging or looping. The genes crucial to directing cardiac asymmetry include a subset of those needed for patterning the dorsoventral axis and for notochord and ventral spinal cord development. Thus, the pattern of cardiac BMP4 appears to be in the pathway by which the heart interprets lateralizing signals from the midline.

Brand
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Beuchle
D.
,
Lun
K.
,
Furutani-Seiki
M.
,
Granato
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Odenthal
J.
,
van Eeden
F. J.
,
Nusslein-Volhard
C.
(
1996
)
Mutations in zebrafish genes affecting the formation of the boundary between midbrain and hindbrain.
Development
123
,
179
90
Brand
M.
,
Heisenberg
C. P.
,
Warga
R. M.
,
Pelegri
F.
,
Karlstrom
R. O.
,
Beuchle
D.
,
Picker
A.
,
Jiang
Y. J.
,
Furutani-Seiki
M.
,
van Eeden
F. J.
,
Granato
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Odenthal
J.
,
Nusslein-Volhard
C.
(
1996
)
Mutations affecting development of the midline and general body shape during zebrafish embryogenesis.
Development
123
,
129
42
Brown
N. A.
,
Wolpert
L.
(
1990
)
The development of handedness in left/right asymmetry.
Development
109
,
1
9
Chen
J.-N.
,
Fishman
M. C.
(
1996
)
Zebrafish tinman homolog demarcates the heart field and initiates myocardial differentiation.
Development
122
,
3809
16
Chen
J.-N.
,
Haffter
P.
,
Odenthal
J.
,
Vogelsang
E.
,
Brand
M.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Hammerschmidt
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Nusslein-Volhard
C.
(
1996
)
Mutations affecting the cardiovascular system and other internal organs in zebrafish.
Development
123
,
293
302
Chiang
C.
,
Litingtung
Y.
,
Lee
E.
,
Young
K. E.
,
Corden
J. L.
,
Westphal
H.
,
Beachy
P. A.
(
1996
)
Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.
Nature
383
,
407
13
Currie
P. D.
,
Ingham
P. W.
(
1996
)
Induction of a specific muscle cell type by a hedgehog-like protein in zebrafish.
Nature
382
,
452
5
Danos
M. C.
,
Yost
H. J.
(
1995
)
Linkage of cardiac left-right asymmetry and dorsal-anterior development in Xenopus.
Development
121
,
1467
74
Danos
M. C.
,
Yost
H. J.
(
1996
)
Role of notochord in specification of cardiac left-right orientation in zebrafish and Xenopus.
Dev. Biol
177
,
96
103
Fishman
M. C.
,
Chien
K. R.
(
1997
)
Fashioning the vertebrate heart: earliest embryonic decisons.
Development
124
,
2099
2177
Fishman
M. C.
,
Stainier
D. Y.
(
1994
)
Cardiovascular development. Prospects for a genetic approach.
Circulation Research
74
,
757
63
Graff
J. M.
,
Thies
R. S.
,
Song
J. J.
,
Celeste
A. J.
,
Melton
D. A.
(
1994
)
Studies with a Xenopus BMP receptor suggest that ventral mesoderm-inducing signals override dorsal signals in vivo.
Cell
79
,
169
79
Granato
M.
,
van Eeden
F. J.
,
Schach
U.
,
Trowe
T.
,
Brand
M.
,
Furutani-Seiki
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Odenthal
J.
,
Nusslein-Volhard
C.
(
1996
)
Genes controlling and mediating locomotion behavior of the zebrafish embryo and larva.
Development
123
,
399
413
Haffter
P.
,
Granato
M.
,
Brand
M.
,
Mullins
M. C.
,
Hammerschmidt
M.
,
Kane
D. A.
,
Odenthal
J.
,
van Eeden
F. J.
,
Jiang
Y. J.
,
Heisenberg
C. P.
,
Kelsh
R. N.
,
Furutani-Seiki
M.
,
Vogelsang
E.
,
Beuchle
D.
,
Schach
U.
,
Fabian
C.
,
Nusslein-Volhard
C.
(
1996
)
The identification of genes with unique and essential functions in the development of the zebrafish, Danio rerio.
Development
123
,
1
36
Halpern
M. E.
,
Ho
R. K.
,
Walker
C.
,
Kimmel
C. B.
(
1993
)
Induction of muscle pioneers and floor plate is distinguished by the zebrafish no tail mutation.
Cell
75
,
99
111
Halpern
M. E.
,
Thisse
C.
,
Ho
R. K.
,
Thisse
B.
,
Riggleman
B.
,
Trevarrow
B.
,
Weinberg
E. S.
,
Postlethwait
J. H.
,
Kimmel
C. B.
(
1995
)
Cell-autonomous shift from axial to paraxial mesodermal development in zebrafish floating head mutants.
Development
121
,
4257
64
Hammerschmidt
M.
,
Brook
A.
,
McMahon
A. P.
(
1997
)
The world according to hedgehog.
Trends in Genetics
13
,
14
21
Hammerschmidt
M.
,
Pelegri
F.
,
Mullins
M. C.
,
Kane
D. A.
,
Brand
M.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Haffter
P.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kelsh
R. N.
,
Odenthal
J.
,
Warga
R. M.
,
Nusslein-Volhard
C.
(
1996
)
Mutations affecting morphogenesis during gastrulation and tail formation in the zebrafish, Danio rerio.
Development
123
,
143
51
Hammerschmidt
M.
,
Pelegri
F.
,
Mullins
M. C.
,
Kane
D. A.
,
van Eeden
F. J.
,
Granato
M.
,
Brand
M.
,
Furutani-Seiki
M.
,
Haffter
P.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kelsh
R. N.
,
Odenthal
J.
,
Warga
R. M.
,
Nusslein-Volhard
C.
(
1996
)
dino and mercedes, two genes regulating dorsal development in the zebrafish embryo.
Development
123
,
95
102
Hammerschmidt
M.
,
Serbedzija
G. N.
,
McMahon
A. P.
(
1996
)
Genetic analysis of dorsoventral pattern formation in the zebrafish: requirement of a BMP-like ventralizing activity and its dorsal repressor.
Genes & Development
10
,
2452
61
Hatta
K.
,
Kimmel
C. B.
,
Ho
R. K.
,
Walker
C.
(
1991
)
The cyclops mutation blocks specification of the floor plate of the zebrafish central nervous system.
Nature
350
,
339
341
Hatta
K.
,
Puschel
A. W.
,
Kimmel
C. B.
(
1994
)
Midline signaling in the primordium of the zebrafish anterior central nervous system.
Proc. Nat. Acad. Sci. USA
91
,
2061
5
Heisenberg
C. P.
,
Brand
M.
,
Jiang
Y. J.
,
Warga
R. M.
,
Beuchle
D.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Odenthal
J.
,
Nusslein-Volhard
C.
(
1996
)
Genes involved in forebrain development in the zebrafish, Danio rerio.
Development
123
,
191
203
Hyatt
B. A.
,
Lohr
J. L.
,
Yost
H. J.
(
1996
)
Initiation of vertebrate left-right axis formation by maternal Vg1.
Nature
384
,
62
5
Isaac
A.
,
Sargent
M. G.
,
Cooke
J.
(
1997
)
Control of vertebrate left-right asymmetry by a snail-related zinc finger gene.
Science
275
,
1301
4
Jiang
Y. J.
,
Brand
M.
,
Heisenberg
C. P.
,
Beuchle
D.
,
Furutani-Seiki
M.
,
Kelsh
R. N.
,
Warga
R. M.
,
Granato
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Kane
D. A.
,
Mullins
M. C.
,
Odenthal
J.
,
van Eeden
F. J.
,
Nusslein-Volhard
C.
(
1996
)
Mutations affecting neurogenesis and brain morphology in the zebrafish, Danio rerio.
Development
123
,
205
16
Kane
D. A.
,
Hammerschmidt
M.
,
Mullins
M. C.
,
Maischein
H. M.
,
Brand
M.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Haffter
P.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kelsh
R. N.
,
Odenthal
J.
,
Warga
R. M.
,
Nusslein-Volhard
C.
(
1996
)
The zebrafish epiboly mutants.
Development
123
,
47
55
Kane
D. A.
,
Maischein
H. M.
,
Brand
M.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Odenthal
J.
,
Warga
R. M.
,
Nusslein-Volhard
C.
(
1996
)
The zebrafish early arrest mutants.
Development
123
,
57
66
Kelsh
R. N.
,
Brand
M.
,
Jiang
Y. J.
,
Heisenberg
C. P.
,
Lin
S.
,
Haffter
P.
,
Odenthal
J.
,
Mullins
M. C.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Hammerschmidt
M.
,
Kane
D. A.
,
Warga
R. M.
,
Beuchle
D.
,
Vogelsang
L.
,
Nusslein-Volhard
C.
(
1996
)
Zebrafish pigmentation mutations and the processes of neural crest development.
Development
123
,
369
89
Kimmel
C. B.
,
Kane
D. A.
,
Walker
C.
,
Warga
R. M.
,
Rothman
M. B.
(
1989
)
A mutation that changes cell movement and cell fate in the zebrafish embryo.
Nature
337
,
358
362
Layton
W. M.
Jr
(
1976
)
Random determination of a developmental process: reversal of normal visceral asymmetry in the mouse.
J. Heredity
67
,
336
8
Levin
M.
,
Johnson
R. L.
,
Stern
C. D.
,
Kuehn
M.
,
Tabin
C.
(
1995
)
A molecular pathway determining left-right asymmetry in chick embryogenesis.
Cell
82
,
803
14
Meno
C.
,
Saijoh
Y.
,
Fujii
H.
,
Ikeda
M.
,
Yokoyama
T.
,
Yokoyama
M.
,
Toyoda
Y.
,
Hamada
H.
(
1996
)
Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos.
Nature
381
,
151
5
Mullins
M. C.
,
Hammerschmidt
M.
,
Kane
D. A.
,
Odenthal
J.
,
Brand
M.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Haffter
P.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kelsh
R. N.
,
Nusslein-Volhard
C.
(
1996
)
Genes establishing dorsoventral pattern formation in the zebrafish embryo: the ventral specifying genes.
Development
123
,
81
93
Odenthal
J.
,
Haffter
P.
,
Vogelsang
E.
,
Brand
M.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Hammerschmidt
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Warga
R. M.
,
Allende
M. L.
,
Weinberg
E. S.
,
Nusslein-Volhard
C.
(
1996
)
Mutations affecting the formation of the notochord in the zebrafish, Danio rerio.
Development
123
,
103
15
Odenthal
J.
,
Rossnagel
K.
,
Haffter
P.
,
Kelsh
R. N.
,
Vogelsang
E.
,
Brand
M.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Hammerschmidt
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kane
D. A.
,
Mullins
M. C.
,
Nusslein-Volhard
C.
(
1996
)
Mutations affecting xanthophore pigmentation in the zebrafish, Danio rerio.
Development
123
,
391
8
Piotrowski
T.
,
Schilling
T. F.
,
Brand
M.
,
Jiang
Y. J.
,
Heisenberg
C. P.
,
Beuchle
D.
,
Grandel
H.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Odenthal
J.
,
Warga
R. M.
,
Nusslein-Volhard
C.
(
1996
)
Jaw and branchial arch mutants in zebrafish II: anterior arches and cartilage differentiation.
Development
123
,
345
56
Ransom
D. G.
,
Haffter
P.
,
Odenthal
J.
,
Brownlie
A.
,
Vogelsang
E.
,
Kelsh
R. N.
,
Brand
M.
,
van Eeden
F. J.
,
Furutani-Seiki
M.
,
Granato
M.
,
Hammerschmidt
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kane
D. A.
,
Mullins
M. C.
,
Nusslein-Volhard
C.
(
1996
)
Characterization of zebrafish mutants with defects in embryonic hematopoiesis.
Development
123
,
311
9
Schilling
T. F.
,
Piotrowski
T.
,
Grandel
H.
,
Brand
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Beuchle
D.
,
Hammerschmidt
M.
,
Kane
D. A.
,
Mullins
M. C.
,
van Eeden
F. J.
,
Kelsh
R. N.
,
Furutani-Seiki
M.
,
Granato
M.
,
Haffter
P.
,
Odenthal
J.
,
Warga
R. M.
,
Trowe
T.
,
Nusslein-Volhard
C.
(
1996
)
Jaw and branchial arch mutants in zebrafish I: branchial arches.
Development
123
,
329
44
Stainier
D. Y.
,
Fouquet
B.
,
Chen
J.-N.
,
Warren
K. S.
,
Weinstein
B. M.
,
Meiler
S. E.
,
Mohideen
M. A.
,
Neuhauss
S. C.
,
Solnica-Krezel
L.
,
Schier
A. F.
,
Zwartkruis
F.
,
Stemple
D. L.
,
Malicki
J.
,
Driever
W.
,
Fishman
M. C.
(
1996
)
Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo.
Development
123
,
285
92
Stainier
D. Y. R.
,
Fishman
M. C.
(
1992
)
Patterning the zebrafish heart tube: Acquisition of anteroposterior polarity.
Dev. Biol
153
,
91
101
Taber
L. A.
,
Lin
I. E.
,
Clark
E. B.
(
1995
)
Mechanics of cardiac looping.
Dev. Dynamics
203
,
42
50
Talbot
W. S.
,
Trevarrow
B.
,
Halpern
M. E.
,
Melby
A. E.
,
Farr
G.
,
Postlethwait
J. H.
,
Jowett
T.
,
Kimmel
C. B.
,
Kimelman
D.
(
1995
)
A homeobox gene essential for zebrafish notochord development.
Nature
378
,
150
7
Ticho
B. S.
,
Stainier
D. Y. R.
,
Fishman
M. C.
,
Breitbart
R.
(
1996
)
Three zebrafish MEF2 genes delineate somitic and cardiac muscle development in wild-type and mutant embryos.
Mech. Dev
59
,
205
218
Trowe
T.
,
Klostermann
S.
,
Baier
H.
,
Granato
M.
,
Crawford
A. D.
,
Grunewald
B.
,
Hoffmann
H.
,
Karlstrom
R. O.
,
Meyer
S. U.
,
Muller
B.
,
Richter
S.
,
Nusslein-Volhard
C.
,
Bonhoeffer
F.
(
1996
)
Mutations disrupting the ordering and topographic mapping of axons in the retinotectal projection of the zebrafish, Danio rerio.
Development
123
,
439
50
Tsuda
T.
,
Philp
N.
,
Zile
M. H.
,
Linask
K. K.
(
1996
)
Left-right asymmetric localization of flectin in the extracellular matrix during heart looping.
Dev. Biol
173
,
39
50
van Eeden
F. J.
,
Granato
M.
,
Schach
U.
,
Brand
M.
,
Furutani-Seiki
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Odenthal
J.
,
Warga
R. M.
,
Allende
M. L.
,
Weinberg
E. S.
,
Nusslein-Volhard
C.
(
1996
)
Mutations affecting somite formation and patterning in the zebrafish, Danio rerio.
Development
123
,
153
64
van Eeden
F. J.
,
Granato
M.
,
Schach
U.
,
Brand
M.
,
Furutani-Seiki
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Odenthal
J.
,
Warga
R. M.
,
Nusslein-Volhard
C.
(
1996
)
Genetic analysis of fin formation in the zebrafish, Danio rerio.
Development
123
,
255
62
Whitfield
T. T.
,
Granato
M.
,
van Eeden
F. J.
,
Schach
U.
,
Brand
M.
,
Furutani-Seiki
M.
,
Haffter
P.
,
Hammerschmidt
M.
,
Heisenberg
C. P.
,
Jiang
Y. J.
,
Kane
D. A.
,
Kelsh
R. N.
,
Mullins
M. C.
,
Odenthal
J.
,
Nusslein-Volhard
C.
(
1996
)
Mutations affecting development of the zebrafish inner ear and lateral line.
Development
123
,
241
54
Yokoyama
T.
,
Copeland
N. G.
,
Jenkins
N. A.
,
Montgomery
C. A.
,
Elder
F. F.
,
Overbeek
P. A.
(
1993
)
Reversal of left-right asymmetry: a situs inversus mutation.
Science
260
,
679
82
Yost
H. J.
(
1995
)
Vertebrate left-right development.
Cell
82
,
689
692
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