We have compared the transcript distribution of cellular retinoic acid binding protein (CRABP) I and II genes in mouse embryos at various stages of development. Both CRABP transcripts are present in embryonic structures from the earliest stages studied and exhibit specific patterns of distribution, suggesting that the two retinoic acid (RA) binding proteins perform different functions during mouse embryogenesis. The CRABP I transcript distribution correlates well with structures known to be targets of excess retinoid-induced teratogenesis (e.g. neural crest cells and hindbrain), suggesting that cells expressing CRABP I are those that cannot tolerate high levels of RA for their normal developmental function. The embryonic structures expressing CRABP II transcripts include those structures that have been shown to be adversely affected by excess of retinoids, such as limbs and hindbrain, but CRABP II transcripts are also found in structures not known to be specifically vulnerable to raised RA levels. The CRABP II gene is coexpressed with retinoic acid receptor (RAR)-beta and cellular retinol binding protein (CRBP) I genes in a number of tissues such as the gut endoderm, hypophysis and interdigital mesenchyme, all of which are devoid of CRABP I transcripts. Interestingly, the expression of the three genes, RAR-beta, CRABP II and CRBP I, is induced by retinoic acid, which suggests a link between the synthesis of RA from retinol and the control of expression of subsets of RA-responsive genes. The transcript distribution of CRABP I and II is discussed in relation to the teratogenic effects of RA, and compared to the RA-sensitive pattern of expression of other important developmental genes.

Bartelmez
G. W.
(
1923
)
The subdivisions of the neural folds in man.
J. Comp. Neurol
35
,
231
247
Benbrook
D.
,
Lernhardt
E.
,
Pfahl
M.
(
1988
)
A new retinoic acid receptor from a hepatocellular carcinoma.
Nature
333
,
669
672
Blomhoff
R.
,
Gree
M. H.
,
Berg
T.
,
Norum
K. R.
(
1990
)
Transport and storage of vitamin A.
Science
250
,
339
404
Boylan
J. F.
,
Gudas
L. J.
(
1991
)
Overexpression of the cellular retinoic acid binding protein-I (CRABP-I) results in a reduction in differentiation-specific gene expression in F9 teratocarcinoma cells.
J.Cell Biol
112
,
965
979
Brand
N.
,
Petkovich
M.
,
Krust
A.
,
Chambon
P.
,
de The
H.
,
Marchio
A.
,
Tiollais
P.
,
Dejean
A.
(
1988
)
Identification of a second human retinoic acid receptor.
Nature
332
,
850
853
Brockes
J.
(
1991
)
We may not have a morphogen.
Nature
350
,
15
–.
Cuschieri
A.
,
Bannister
L. H.
(
1975
)
The development of the olfactory mucosa in the mouse: light microscopy.
J. Anat
119
,
277
286
Dencker
L.
,
Annerwall
E.
,
Busch
C.
,
Eriksson
U.
(
1990
)
Localization of specific retinoid-binding sites and expression of cellular retinoic-acid binding protein (CRABP) in the early mouse embryo.
Development
110
,
343
352
de The
H.
,
Vivanco Ruiz
M. M.
,
Tiollais
P.
,
Stunnenberg
H.
,
Dejean
A.
(
1990
)
Identification of a retinoic acid responsive element in the retinoic acid receptorgene.
Nature
343
,
177
180
Dolle
P.
,
Izpisua-Belmonte
J. C.
,
Falkenstein
H.
,
Renucci
A.
,
Duboule
D.
(
1989
)
Coordinate expression of the murine Hox-5 complex homeobox-containing genes during limb pattern formation.
Nature
342
,
767
772
Dolle
P.
,
Ruberte
E.
,
Kastner
P.
,
Petkovich
M.
,
Stoner
C. M.
,
Gudas
L. J.
,
Chambon
P.
(
1989
)
Differential expression of the genes encoding the retinoic acid receptors, and CRABP I in the developing limbs of the mouse.
Nature
342
,
702
705
Dolle
P.
,
Ruberte
E.
,
Leroy
P.
,
Morriss-Kay
G. M.
,
Chambon
P.
(
1990
)
Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis.
Development
110
,
1133
1151
Giguere
V.
,
Lyn
S.
,
Yip
P.
,
Siu
C. H.
,
Evans
R. M.
(
1990
)
Molecular cloning of cDNA encoding a second cellular retinoic acid-binding protein.
Proc. Natl. Acad. Sci. USA
87
,
6233
6237
Giguere
V.
,
Ong
E. S.
,
Segui
P.
,
Evans
R. M.
(
1987
)
Identification of a receptor for the morphogen retinoic acid.
Nature
330
,
624
629
Hunt
P.
,
Faiella
A.
,
Cook
M.
,
Sham
M.-H.
,
Gulisano
M.
,
Wilkinson
D.
,
Boncinelli
E.
,
Krumlauf
R.
(
1991
)
A distinct Hox code for the branchial region of the head.
Nature
353
,
861
864
Izpisúa-Belmonte
J.-C.
,
Tickle
C.
,
Dolle
P.
,
Wolpert
L.
,
Duboule
D.
(
1991
)
Expression of the homeobox Hox-4 genes and specification of position in chick wing development.
Nature
350
,
585
589
Lammer
G. J.
,
Chen
D. T.
,
Hoar
R. M.
,
Agnish
N. D.
,
Benke
P. J.
,
Braun
J. T.
,
Curry
C. J.
,
Fernhoff
P. M.
,
Grix
A. W.
,
Lott
I. T.
,
Richard
J. M.
,
Sun
S. C.
(
1985
)
Retinoic acid embryopathy.
New England J. Med
333
,
837
841
Maden
M.
,
Ong
D. E.
,
Summerbell
D.
,
Chytil
F.
(
1988
)
Spatial distribution of cellular protein binding to retinoic acid in the chick limb bud.
Nature
335
,
733
735
Mark
M. P.
,
Bloch-Zupan
A.
,
Wolf
C.
,
Ruberte
E.
,
Ruch
J. V.
(
1991
)
Involvement of cellular retinoic acid-binding proteins I and II (CRABP I and CRABP II) and of the cellular retinol-binding protein I (CRBP) in odontogenesis in the mouse.
Differentiation
48
,
89
98
Mavilio
F.
,
Simeone
A.
,
Boncinelli
E.
,
Andrews
P. W.
(
1988
)
Activation of four homeobox gene clusters in human embryonal carcinoma cells induced to differentiate by retinoic acid.
Differentiation
37
,
73
79
Morriss
G. M.
(
1972
)
Morphogenesis of the malformations induced in rat embryos by maternal hypervitaminosis A.
J. Anat
113
,
241
250
Morriss-Kay
G. M.
,
Murphy
P.
,
Davidson
D. R.
,
Hill
R. E.
(
1991
).
Effects of retinoic acid excess on expression of Hox-2.9 and Krox-20 and on morphological segmentation in the hindbrain of mouse embryos.
EMBO J
10
,
2985
2995
Muller
F.
,
O'Rahilly
R.
(
1985
)
The first appearance of the neural tube and optic primordium in the human embryo at stage 10.
Anat. Embryol
172
,
157
169
Murphy
P.
,
Davidson
D. R.
,
Hill
R. E.
(
1989
)
Segment-specificE. Ruberte and others987CRABPI and II expression in mouse embryosexpression of a homeobox-containing gene in the mouse hindbrain.
Nature
341
,
156
159
Murphy
P.
,
Hill
R. E.
(
1991
).
Expression of the mouse labial-like homeobox containing genes, Hox 2.9 and Hox 1.6, during segmentation of the hindbrain.
Development
111
,
61
74
Nichols
D. H.
(
1981
)
Neural crest formation in the head of the mouse embryo as observed using a new histological technique.
J. Embryol. exp. Morph
64
,
105
120
Noden
D. M.
(
1978
)
The control of avian cephalic neural crest cytodifferentiation. I. Skeletal and connective tissues.
Dev. Biol
67
,
296
312
Noden
D. M.
(
1978
)
The control of avian cephalic neural crest cytodifferentiation. II. Neural tissues.
Dev. Biol
67
,
313
329
Nohno
T.
,
Noji
S.
,
Koyama
E.
,
Ohyama
K.
,
Myokai
F.
,
Kuroiwa
A.
,
Saito
T.
,
Taniguchi
S.
(
1991
)
Involvement of the Chox-4 chicken homeobox genes in determination of anteroposterior axial polarity during limb development.
Cell
64
,
1197
1205
Noji
S.
,
Nohno
T.
,
Koyama
E.
,
Muto
K.
,
Ohyama
K.
,
Aoki
Y.
,
Tamura
K.
,
Ohsugi
K.
,
Ide
H.
,
Taniguchi
S.
,
Saito
T.
(
1991
)
Retinoic acid induces polarising activity but is unlikely to be a morphogen in the chick limb bud.
Nature
350
,
83
86
Papalopulu
N.
,
Lovell-Badge
R.
,
Krumlauf
R.
(
1991
)
The expression of murine Hox-2 genes is dependent on the differentiation pathway and displays a collinear sensitivity to retinoic acid in F9 cells and Xenopus embryos.
Nucl. Acids Res
19
,
5497
5506
Petkovich
M.
,
Brand
N. J.
,
Krust
A.
,
Chambon
P.
(
1987
)
A human retinoic acid receptor which belongs to the family of nuclear receptors.
Nature
330
,
444
450
Robertson
M.
(
1987
)
Towards a biochemistry of morphogenesis.
Nature
330
,
420
421
Rosa
F. W.
,
Wilk
A. L.
,
Kelsey
F. O.
(
1986
)
Teratogen update: vitamin A congeners.
Teratology
33
,
355
364
Ruberte
E.
,
Dolle
P.
,
Chambon
P.
,
Morriss-Kay
G.
(
1991
)
Retinoic acid receptors and cellular retinoid binding proteins II. Their differential pattern of transcription during early morphogenesis in mouse embryos.
Development
111
,
45
60
Ruberte
E.
,
Dolle
P.
,
Krust
A.
,
Zelent
A.
,
Morriss-Kay
G.
,
Chambon
P.
(
1990
)
Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis.
Development
108
,
213
222
Shenefelt
R. E.
(
1972
)
Morphogenesis of malformations in hamster caused by retinoic acid, relation to dose and stage at treatment.
Teratology
5
,
103
108
Simeone
A.
,
Acampora
D.
,
Arcioni
L.
,
Andrews
P. W.
,
Boncinelli
E.
,
Mavilio
F.
(
1990
)
Sequential activation of human HOX-2 homeobox genes by retinoic acid in embryonal carcinoma cells.
Nature
346
,
763
766
Simeone
D.
,
Acampora
V.
,
Nigro
A.
,
Faiella
M.
,
D'Esposito
A.
,
Stornaiuolo
F.
,
Mavilio
F.
,
Boncinelli
E.
(
1991
)
Differentialregulation by retinoic acid of the homeobox genes of the four HOX loci in human embryonal carcinoma cells.
Mech. of Dev
33
,
215
227
Smith
S. M.
,
Pang
K.
,
Sundin
O.
,
Wedden
S. E.
,
Thaller
C.
,
Eichele
G.
(
1989
)
Molecular approaches to vertebrate limb morphogenesis.
Development
107
,
121
131
Smith
W. C.
,
Nakshatri
H.
,
Leroy
P.
,
Rees
J.
,
Chambon
P.
(
1991
)
A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBP I) promoter.
EMBO J
10
,
2223
2230
Stoner
C. M.
,
Gudas
L. J.
(
1989
)
Mouse cellular retinoic acid binding protein: cloning, complementary DNA sequence, and messenger RNA expression during the retinoic acid induced differentiation of F9 wild type and RA-3-10 mutant teratocarcinoma.
Cancer Research
49
,
1497
1504
Summerbell
D.
,
Lewis
J. H.
(
1975
)
Time, place and positional value in the chick limb-bud.
J. Embryol. exp. Morph
33
,
621
643
Tabin
C. J.
(
1991
)
Retinoids, homeoboxes, and growth factors: towards molecular models for limb development.
Cell
66
,
199
217
Takase
S.
,
Ong
D. E.
,
Chytil
F.
(
1986
)
Transfer of RA from its complex with cellular retinoic acid binding protein to the nucleus.
Arch. Biochem. Biophys
247
,
328
–.
Tan
S. S.
,
Morriss-Kay
G. M.
(
1986
)
Analysis of cranial neural crest cell migration and early fates in postimplantation rat chimeras.
J. Embryol. exp. Morph
98
,
21
58
Vaessen
M. J.
,
Meijers
J. H. C.
,
Bootsma
D.
,
van Kessel
A. G.
(
1990
)
The cellular retinoid binding protein is expressed in tissues associated with retinoic acid induced malformations.
Development
110
,
371
378
Warkany
J.
,
Nelson
R. C.
,
Schraffenberger
E.
(
1943
)
Congenital malformations induced in rats by maternal nutritional deficiency. III. The malformations of the extremities.
J. Bone and Joint Surg
5
,
261
270
Wilkinson
D. G.
,
Bhatt
S.
,
Chavrier
P.
,
Bravo
R.
,
Charnay
P.
(
1989
)
Segment-specific expression of a zinc-finger gene in the developing nervous system of the mouse.
Nature
337
,
461
464
Wilkinson
D. G.
,
Bhatt
S.
,
Cook
M.
,
Boncinelli
E.
,
Krumlauf
R.
(
1989
)
Segmental expression of Hox-2 homeobox containing genes in the developing mouse hindbrain.
Nature
341
,
405
409
Wilkinson
D. G.
,
Peters
G.
,
Dickson
C.
,
MacMahon
A. P.
(
1988
)
Expression of the FGF-related proto-oncogene int-2 during gastrulation and neurulation in the mouse.
EMBO J
7
,
691
695
Wilson
J. G.
,
Roth
C. B.
,
Warkany
J.
(
1953
)
An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration at various times during gestation.
Am. J. Anat
92
,
189
217
Yokouchi
Y.
,
Sasaki
H.
,
Kuroiwa
A.
(
1991
)
Homeobox expression correlated with the bifurcation process of limb cartilage development.
Nature
353
,
443
445
Zelent
A.
,
Krust
A.
,
Petkovich
M.
,
Kastner
P.
,
Chambon
P.
(
1989
)
Cloning of murineand retinoic acid receptors and a novel receptorpredominantly expressed in the skin.
Nature
339
,
714
717
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