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Physiological Reviews about Additional material and information /publications/prv This information is current as of January 7, 2010 . /.20814-3991. Copyright © 2005 by the American Physiological Society. ISSN: 0031-9333, ESSN: 1522-1210. Visit our website at MD published quarterly in January, April, July, and October by the American Physiological Society, 9650 Rockville Pike, Bethesda provides state of the art coverage of timely issues in the physiological and biomedical sciences. It is Physiological Reviews on January 7, 2010
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Retinoids in Embryonal Development
SHARON A.ROSS,PETER J.M C CAFFERY,URSULA C.DRAGER,AND LUIGI M.DE LUCA
Food and Drug Administration,Center for Food Safety and Applied Nutrition,Office of Nutritional Products,
Labeling,and Dietary Supplements,Washington,DC;E.Kennedy Shriver Center,Waltham;Department
of Psychiatry,Harvard Medical School,Boston,Massachutts;and National Cancer Institute,
National Institutes of Health,Bethesda,Maryland
I.Introduction 1022II.Retinoid Structure 1022III.Retinoid Requirement During Embryogenesis 1022
A.Introduction 1022
B.Retinoid ligand knockout models 1024IV.Metabolism 1025
A.Introduction 1025
B.Retinol dehydrogena 1026
C.Retinaldehyde dehydrogenas 1027
D.Synthesis of other bioactive retinoids in the embryo 1029
E.Influence of substrate concentration and distribution 1029
F.RA catabolism 1029
G.Retinoid binding proteins 1030
H.Hypothesis:CRABP captures RA for cells that lack RA synthesis 1030V.Retinoid Receptors/Function 1031
A.Introduction 1031
B.Speculations on orders of receptor interactions 1031
C.Receptors and embryogenesis 1033VI.Retinoid Receptor Knockout Mutants 1033
A.Isoform-specific knockouts 1033
B.Single subtype knockouts 1033
C.Double/compound mutants 1034
D.Retinoid receptor mutants and limb malformations 1035
E.Retinoid receptor mutants and malformations of the vertebral column 1035
F.Respon of mutants to excess RA 1036
G.Conclusions of mutant mice studies 1036VII.Hox Genes and Retinoids in Development 1037
A.Hox genes in development 1037
B.Retinoids and Hox genes 1037
曾春年演唱会
C.Conclusions on the induction of Hox genes by retinoids 1039VIII.Teratology/Excess Retinoids 1039
A.Introduction 1039
B.Retinoids and limb morphogenesis 1039
C.Animal teratogenic models 1040
D.Molecular mechanism of excess retinoids in teratogenesis 1041
E.Prescription oral retinoids as teratogens in humans 1041
F.Human epidemiological evidence:intake of vitamin A and risk of birth defects 1043IX.Conclusions and Future Aspects 1046Ross,Sharon A.,Peter J.McCaffery,Ursula C.Drager,and Luigi M.De Luca.Retinoids in Embryonal Development.Physiol Rev 80:1021–1054,2000.—The key role of vitamin A in embryonal development is reviewed.Special emphasis is given to the physiological action of retinoids,as evident from the retinoid ligand knockout models.Retinoid metabolism in embryonic tissues and teratogenic conquences of retinoid administration at high dos are prented.Physiological and pharmacological actions of retinoids are outlined and explained on the basis of their interactions as ligands of the nuclear retinoid receptors.Immediate target genes and the retinoid respon
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elements of their promoters are summarized.The fundamental role of homeobox genes in embryonal development and the actions of retinoids on their expression are discusd.The similarity of the effects of retinoid ligand knockouts to effects of compound retinoid receptor knockouts on embryogenesis is prented.Although much remains to be clarified,the emerging landscape offers exciting views for future rearch.
I.INTRODUCTION
Vitamin A and its derivatives (the retinoids)are es-
ntial for both normal embryonic development (87)and
maintenance of differentiation in the adult organism (35,
36,78),accounting for the inten interest in the com-
pounds in biology and medicine.Embryo gmentation
and growth fail,vascularization stops,and the embryo is
eventually resorbed in the abnce of sufficient vitamin A
(151,279,297).Excess vitamin A,on the other hand,
results in terata during embryogenesis and is membrano-
lytic and hepatotoxic in the adult organism (204).In the
adult,epithelial differentiation requires vitamin A.Its de-
ficiency caus squamous metaplasia,a preneoplastic le-
sion,which eventually also alters functional epithelial
characteristics and leads to infection and death (36,247,
306).The considerations make it obvious that mainte-
nance of retinoid homeostasis is tantamount to mainte-
nance of normal physiology of the intact organism.
The u of the retinoid ligand knockout models to
study embryonic development has unequivocally linked
the physiological function of vitamin A to development of
the heart,the embryonal circulation,the central nervous
system (CNS),and the normal left-to-right cardiac sym-
metry (321).Recent work has also emphasized that the
developmentally regulated generation of bioactive reti-
noids is fundamental to the control of embryonic devel-
opment (47,321).
Remarkable progress has occurred in the past 10
years in our understanding of the mode of action of
vitamin A and its derivatives,the retinoids (37).The dis-
covery of the nuclear receptors for retinoic acid and other
retinoids has provided a conceptual basis to explain how
the compounds preside over a large network of gene
activation process (35).
It is the purpo of this review to prent a balanced
synopsis of the actions of retinoids in embryonal devel-
显卡降温opment and to provide suggestions for future studies.
II.RETINOID STRUCTURE
Figure 1shows the chemical structure of the salient,
physiologically important retinoids so far identified.The
parent compound retinol and its oxidation product,reti-
noic acid (RA),are shown in the stretched-out all -trans -
configuration at the top of the figure.Derivatives of reti-
nol include 4-hydroxy-retinol,4-oxo-retinol,and 14-
hydroxy-4,14-retro-retinol.Of the RA derivatives,
4-hydroxy-RA,4-oxo-RA,3,4-didehydro-RA (ddRA),and the rexinoid receptor (RXR)ligand 9-cis -RA are shown.All -trans RA is the natural ligand for the retinoic acid receptors (RAR)(71,221),and 9-cis -RA for the RXR (137),although the latter compound binds to both receptor fam-ilies.The specificity of interactions would also suggest the possibility that various retinoids,both natural and syn-thetic,may specifically be uful as drugs to combat diver dias.III.RETINOID REQUIREMENT DURING EMBRYOGENESIS A.Introduction Retinol (also referred to as ROL and/or vitamin A)is the only retinoid known to be capable of sustaining all vitamin A functions,including development,growth,vi-sion,and reproduction (Fig.2).On the other hand,RA maintains differentiation and growth of the adult
organ-ism;it,however,is insufficient to support gestation of the embryo.Becau RA cannot fulfill all vitamin A functions,it is obvious that veral retinoids,in addition to RA and which are not RA metabolites,act in concert to maintain the health and well being of the entire organism.Also possible are limitations of cellular metabolism and trans-port,where cells require RA but must transport retinol across a tissue barrier.For a more detailed discussion of the different roles of vitamin A,the reader is referred to the following reviews (11,263,307).As early as the 1930s it was realized that maternal insufficiency of vitamin A results in death of the fetus as well as congenital malformations (79,172).Later,Wilson and co-workers (279,305)defined congenital abnormali-ties resulting from vitamin A deficiency during gestation.Teratogenic targets of vitamin A deficiency were the heart,ocular tissues,and respiratory,urogenital and cir-culatory systems (321).The abnormalities were pre-vented by inclusion of vitamin A in the diet.Excess dietary vitamin A,on the other hand,has been shown to also cau teratogenesis (26).Several other studies followed this original obrvation and are dis-cusd in ction VIII .Suffice it to say here that major excess vitamin A targets include the heart,the skull,skeleton,limbs,brain,eyes,CNS,as well as craniofacial structures (15,110,111,189,191,203,234,252,322).Similarity of teratogenic respons between vitamin A deficiency and excess supports the concept that the same molecules are involved.It also suggests a fundamen-tal role for this nutrient in embryonal development.
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The work of Wellick and De Luca (297)has demon-
strated that retinol is esntial and RA alone appears
insufficient to allow gestation in the rat to reach comple-
tion.In fact,vitamin A-deficient pregnant rats resorb their
fetus at about day 15of gestation ,even if given retinoic
acid daily.Retinol,on the other hand,prevents this re-
sorption when administered no later than day 10of ges-
tation.In fact,the administration of as little as 2g on
day 10is sufficient to allow continuation of gestation
through parturition (298).Claggett-Dame recently pro-
pod that extremely high RA dos may,in fact,rescue
the dpc 14.5gestational barrier identified by Wellick and
De Luca (298).Whether this reflects rescue by traces of
alternative retinoids in not known at this time.Countering
this is Niederreither’s RALDH2knockout,which is incom-
pletely rescued by exogenous RA (206,207).
The recommended dietary allowance (RDA)for vita-
min A for nonpregnant and pregnant women is 800g RA,
which is equivalent to ϳ2,700IU (210).No increment of
vitamin A is recommended during pregnancy (210,214).
For a discussion of the data which justify this recom-mended intake,the reader is referred to the 10th edition of the RDA (210).Different retinoid requirements between the avian and mammalian systems have been highlighted and are summa-rized as follows:1)ddRA and its precursor 3,4-didehydro-retinol (ddROH)were undetectable in mou limb buds,although prominent in chick limbs;2)a relatively high con-centration of retinyl esters (1.5M)is evident in chick limb buds but not in mou;and 3)there is a higher concentra-tion of cellular retinoic acid binding proteins (CRABP),es-pecially CRABPII,than their ligands RA and ddRA in both species.Retinol and ddROH,on the other hand,were prent in much higher concentration than cellular retinol binding proteins (CRBP)(245).The concentration of “free”RA was found to be near the range for the dissociation constant (K d )value of the murine RAR.Principal approaches to study the esntial function of vitamin A during embryonal development are exposure to excess retinoid,retinoid receptor knockout studies,and finally retinoid-ligand knockout models.This last ap-proach is discusd in ction III B
.
FIG.
1.Structures of the most com-
mon natural retinoids.July 2000RETINOIDS IN EMBRYONAL DEVELOPMENT 1023
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B.Retinoid Ligand Knockouts Models
The studies of Zile (321)have demonstrated the u-
fulness of the vitamin A-deficient (retinoid ligand knock-
out)avian embryo.The embryos display a strict depen-
dence on vitamin A for their development of early
vasculature.The avian embryos die at 3days of embry-
onic life in the abnce of vitamin A (43,279).After the
initial discovery by Heine et al.(83)that vitamin A is
necessary for the establishment of the early vasculature,
Zile (321)extended the studies to early development.
应聘个人简历模板
Dong and Zile (53)and Chen et al.(25)had established
that RA given to the hen is not transported to the egg.In
this way a completely vitamin A-deficient embryo can be
obtained from hens that are RA sufficient (53).This model
was ud by Zile and collaborators to define primary
target tissues of vitamin A action during embryogenesis.
The vitamin A-deficient quail embryo prents with
gross abnormalities in the cardiovascular system,head,
CNS,hematopoietic organs,and trunk (43,151,152,283,
321,322).Bioactive retinoids can “rescue”the vitamin
A-deficient embryo by preventing abnormal development
when available at early development (43,83,115,117,279,
321).Becau both retinoic excess as well as deficiency
had similar teratogenic effects on the heart,Zile’s group
has launched an in depth investigation of the function of
残疾英语vitamin A in early heart development,using the vitamin
A-deficient quail model (115–117).The studies are of particular interest becau of the obvious relevance to human cardiovascular malformations,which may well be diet-related during pregnancy.Availability of vitamin A may be a relevant contributory element to the incidence of heart
malformation in developing countries,where vi-tamin A deficiency is a significant problem (261).Very little is understood of its etiology in the industrialized world,hence,the importance of better definition of etio-logical factors,especially dietary ones during pregnancy,since diet is likely to contribute the majority of xenobiotic as well as homobiotic factors to the physiology and pa-thology of the body.Vitamin A is also required for normal specification of heart left-right asymmetry.In a large per-centage of vitamin A-deficient quail embryos,the heart appears on the wrong side (randomization)(281,283,284,323).Retinoids,although not directly involved in assign-ing cardiac asymmetry genes to their asymmetry-specific sites,are absolutely esntial for normal heart sidedness to occur (M.H.Zile,personal communication).Impor-tantly,administration of vitamin A to deficient embryos as late as stage 8(neurulation)prevents the anticipated vi-tamin A-deficient phenotype,including situs inversus (43,115,117,323).They propo that the critical retinoid-requiring developmental window is at the four/five-somite stage during neurulation,when retinoid prence is abso-lutely esntial for normal embryonic development to proceed.Excess retinoid resulting from implantation of retinoid impregnated pellets also caus cardiac
abnor-FIG.2.Highlights of the various functions of vitamin A in males and females.
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