alpha 4 integrins are cell surface receptors that mediate cell-extracellular matrix (ECM) and cell-cell adhesions by interacting with fibronectin (FN) and vascular cell adhesion molecule 1 (VCAM-1), respectively. We have generated a null mutation in the gene for the alpha 4 integrin subunit. Homozygous null embryos express no alpha 4 integrins and show two unexpected defects, both of which lead to embryonic lethality. The first defect is failure of fusion of the allantois with the chorion during placentation. The second is in the development of the epicardium and coronary vessels leading to cardiac hemorrhage. Both processes clearly involve alpha 4 integrin interactions that were previously unsuspected. alpha 4 integrin and VCAM-1 are expressed at the sites of these interactions. These results raise the possibility of abortifacients targeting alpha 4 integrins, and raise serious questions about potential side effects of drugs currently being designed to block alpha 4 integrin functions in inflammation.

Adams
J. C.
,
Watt
F. M.
(
1993
)
Regulation of development and differentiation by the extracellular matrix.
Development
117
,
1183
1198
Allavena
P.
,
Paganin
C.
,
Martin-Padura
I.
,
Peri
G.
,
Gaboli
M.
,
Dejana
E.
,
Marchisio
P. C.
,
Mantovani
A.
(
1991
)
Molecules and structures involved in the adhesion of natural killer cells to vascular endothelium.
J. Exp. Med
173
,
439
–.
Berlin
C.
,
Berg
E. L.
,
Briskin
M. J.
,
Andrew
D. P.
,
Kilshaw
P. J.
,
Holzmann
B.
,
Weissman
I. L.
,
Hamann
A.
,
Butcher
E. C.
(
1993
)
4 7integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1.
Cell
74
,
185
195
Bochner
B. S.
,
Luscinskas
F. W.
,
Gimbrone
M. A.
,
Newman
W.
,
Sterbinsky
S. A.
,
Derse-Anthony
C. P.
,
Klunk
D.
,
Schleimer
R. P.
(
1991
)
Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1-activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules.
J. Exp. Med
173
,
1553
–.
Capecchi
M. R.
(
1989
)
Altering the genome by homologous recombination.
Science
244
,
1288
1292
Carlos
T.
,
Kovach
N.
,
Schwartz
B.
,
Rosa
M.
,
Newman
B.
,
Wayner
E.
,
Benjamin
C.
,
Osborn
L.
,
Lobb
R.
,
Harlan
J.
(
1991
)
Human monocytes bind to two cytokine-induced adhesive ligands on cultured human endothelial cells: endothelial-leukocyte adhsion molecule-1 and vascular cell adhesion molecule-1.
Blood
77
,
2266
–.
Chan
B. M.
,
Elices
M. J.
,
Murphy
E.
,
Hemler
M. E.
(
1992
)
Adhesion to vascular cell adhesion molecule 1 and fibronectin. Comparison of4 1(VLA-4) and 47 on the human B cell line JY.
J. Biol. Chem
267
,
8366
8370
Church
G. M.
,
Gilbert
W.
(
1984
)
Genomic sequencing.
Proc. Natl. Acad. Sci. USA
81
,
1991
1995
Doetschman
T. C.
,
Eistetter
H.
,
Katz
M.
,
Schmidt
W.
,
Kemler
R.
(
1985
)
The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium.
J. Embryol. Exp. Morph
87
,
27
45
Dufour
S.
,
Duband
J.-L.
,
Humphries
M. J.
,
Obara
M.
,
Yamada
K. M.
,
Thiery
J. P.
(
1988
)
Attachment, spreading and locomotion of avian neural crest cells are mediated by multiple adhesion sites on fibronectin molecules.
EMBO J
7
,
2661
2671
Elices
M. J.
,
Osborn
L.
,
Takada
Y.
,
Crouse
C.
,
Luhowskyj
S.
,
Hemler
M. E.
,
Lobb
R. R.
(
1990
)
VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site.
Cell
60
,
577
584
George
E. L.
,
Georges
E. N.
,
Patel-King
R. S.
,
Rayburn
H.
,
Hynes
R.O.
(
1993
)
Defects in mesodermal migration and vascular development in fibronectin-deficient mice.
Development
119
,
1079
1091
Guan
J.-L.
,
Hynes
R. O.
(
1990
)
Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor.
Cell
60
,
51
63
Hiruma
T.
,
Hirakow
R.
(
1989
)
Epicardial formation in embryonic chick heart: computer-aided reconstruction, scanning, and transmission electron microscopic studies.
Am. J. Anat
184
,
129
138
Holzmann
B.
,
McIntyre
B. W.
,
Weissman
I. L.
(
1989
)
Identification of a murine Peyer's Patch-specific lymphocyte homing receptor as an integrin molecule with anchain homologous to human VLA-4.
Cell
56
,
37
46
Hynes
R. O.
(
1973
)
Alteration of cell-surface proteins by viral transformation and by proteolysis.
Proc. Natl Acad. Sci. USA
70
,
3170
3174
Hynes
R. O.
(
1992
)
Integrins: versatility, modulation, and signaling in cell adhesion.
Cell
69
,
11
25
Hynes
R. O.
,
Lander
A. D.
(
1992
)
Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons.
Cell
68
,
303
322
Laemmli
U. K.
(
1970
)
Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
Nature
277
,
680
685
Laird
P. W.
,
Zijderveld
A.
,
Linders
K.
,
Rudnicki
M. A.
,
Jaenisch
R.
,
Berns
A.
(
1991
)
Simplified mammalian DNA isolation procedure.
Nucl. Acids Res
19
,
4293
–.
Mansour
S. L.
,
Thomas
K. R.
,
Capecchi
M. R.
(
1988
)
Disruption of the proto-oncogene int-2 in mouse embryo-derive stem cells: a general strategy for targeting mutations to non-selectable genes.
Nature
336
,
348
352
Marcantonio
E. E.
,
Hynes
R. O.
(
1988
)
Antibodies to the conserved cytoplasmic domain of the integrin1subunit react with proteins in vertebrates, invertebrates and fungi.
J. Cell Biol
106
,
1765
1772
Mautner
V. M.
,
Hynes
R. O.
(
1977
)
Surface distribution of LETS protein in relation to the cytoskeleton of normal and transformed fibroblasts.
J. Cell Biol
75
,
743
768
McBurney
M. W.
,
Sutherland
L. C.
,
Adra
C. N.
,
Leclair
B.
,
Rudnicki
M.A.
,
Jardine
K.
(
1991
)
The mouse Pgk-1 gene promotor contains an upstream activator sequence.
Nucl. Acids Res
20
,
5755
5761
Miyake
K.
,
Medina
K.
,
Ishihara
K.
,
Kimoto
M.
,
Auerbach
R.
,
Kincade
P. W.
(
1991
)
A VCAM-like adhesion molecule on murine bone marrow stromal cells mediates binding of lymphocyte precursors in culture.
J. Cell Biol
114
,
557
565
Mould
A.P.
,
Wheldon
L.A.
,
Komoriya
A.
,
Wayner
E.A.
,
Yamada
K.M.
,
Humphries
M.J.
(
1990
)
Affinity chromatographic isolation of the melanoma adhesion receptor for the IIICS region of fibronectin and its identification as the integrin.
J. Biol. Chem
265
,
4020
4024
Osborn
L.
,
Hession
C.
,
Tizard
R.
,
Vassallo
C.
,
Luhowskyj
S.
,
Chi-Rosso
G.
,
Lobb
R.
(
1989
)
Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes.
Cell
59
,
1203
1211
Papayannopoulou
T.
,
Brice
M.
(
1992
)
Integrin expression profiles during erythroid differentiation.
Blood
79
,
1686
1694
Poelmann
R.E.
,
Gittenberger-de Groot
A.C.
,
Mentink
M.M.T.
,
Bokenkamp
R.
,
Hogers
B.
(
1993
)
Development of the cardiac coronary vascular endothelium, studied with antiendothelial antibodies, in chicken-quail chimeras.
Circulation Res
73
,
559
568
Qian
F.
,
Vaux
D. L.
,
Weissman
I. L.
(
1994
)
Expression of the integrin4 1on melanoma cells can inhibit the invasive stage of metastasis formation.
Cell
77
,
335
347
Rosen
G. D.
,
Sanes
J. R.
,
LaChance
R.
,
Cunningham
J. M.
,
Roman
J.
,
Dean
D. C.
(
1992
)
Roles for the integrin VLA-4 and its counter receptor VCAM-1 in myogenesis.
Cell
69
,
1107
1119
Rudnicki
M. A.
,
Braun
T.
,
Hinuma
S.
,
Jaenisch
R.
(
1992
)
Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development.
Cell
71
,
383
390
Ruegg
C.
,
Postigo
A. A.
,
Sikorski
E. E.
,
Butcher
E. C.
,
Pytela
R.
,
Erle
D. J.
(
1992
)
Role of4 7/4 Pintegrin in lymphocyte adherence to fibronectin and VCAM-1 and in homotypic cell clustering.
J. Cell Biol
117
,
179
189
Sheppard
A. M.
,
Onken
M. D.
,
Rosen
G. D.
,
Noakes
P. G.
,
Dean
D. C.
(
1994
)
Expanding Roles for4integrin and its ligands in development.
Cell Adh. Com
2
,
27
43
Springer
T. A.
(
1994
)
Traffic signals for lymphocyte recirculation and leukocyte emigration:the multistep paradigm.
Cell
76
,
301
314
Takada
Y.
,
Elices
M. J.
,
Crouse
C.
,
Hemler
M. E.
(
1989
)
The primary structure of the4subunit of VLA-4: homology to other integrins and a possible cell-cell adhesion function.
EMBO J
8
,
1361
1368
Viragh
S.
,
Challice
C. E.
(
1981
)
The origin of the epicardium and the embryonic myocardial circulation in the mouse.
Anat. Rec
201
,
157
168
Viragh
S.
,
Gittenberger-de Groot
A.C.
,
Poelmann
R.E.
,
Kalman
F.
(
1993
)
Early development of quail heart epicardium and associated vascular and glandular structures.
Anat. Embryol
188
,
381
393
Wayner
E. A.
,
Garcia-Pardo
A.
,
Humphries
M. J.
,
McDonald
J. A.
,
Carter
W. G.
(
1989
)
Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin.
J. Cell Biol
109
,
1321
1330
Williams
D. A.
,
Rios
M.
,
Stephens
C.
,
Patel
V. P.
(
1991
)
Fibronectin and VLA-4 in haematopoietic stem cell-microenvironment interactions.
Nature
352
,
438
441
Yang
J. T.
,
Rayburn
H.
,
Hynes
R. O.
(
1993
)
Embryonic mesodermal defects in5integrin-deficient mice.
Development
119
,
1093
1105
Yednock
T. A.
,
Cannon
C.
,
Fritz
L. C.
,
Sanchez-Madrid
F.
,
Steinman
L.
,
Karin
N.
(
1992
)
Prevention of experimental autoimmune encephalomyelitis by antibodies against4 1integrin.
Nature
356
,
63
66
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