Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb.
Exogenous retinoic acid (RA) induces marked effects on limb patterning, but the precise role of endogenous RA in this process has remained unknown. We have studied the role of RA in mouse limb development by focusing on CYP26B1, a cytochrome P450 enzyme that inactivates RA. Cyp26b1 was shown to be expressed in the distal region of the developing limb bud, and mice that lack CYP26B1 exhibited severe limb malformation (meromelia). The lack of CYP26B1 resulted in spreading of the RA signal toward the distal end of the developing limb and induced proximodistal patterning defects characterized by expansion of proximal identity and restriction of distal identity. CYP26B1 deficiency also induced pronounced apoptosis in the developing limb and delayed chondrocyte maturation. Wild-type embryos exposed to excess RA phenocopied the limb defects of Cyp26b1(-/-) mice. These observations suggest that RA acts as a morphogen to determine proximodistal identity, and that CYP26B1 prevents apoptosis and promotes chondrocyte maturation, in the developing limb.
Yashiro
Kenta
K
Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan.
Zhao
Xianling
X
Uehara
Masayuki
M
Yamashita
Kimiyo
K
Nishijima
Misae
M
Nishino
Jinsuke
J
Saijoh
Yukio
Y
Sakai
Yasuo
Y
Hamada
Hiroshi
H
D000014:Abnormalities, Drug-Induced / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D019521:Body Patterning / Q000187:drug effects / Q000502:physiology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002277:Carcinoma; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004627:Embryonic Induction / Q000187:drug effects / Q000502:physiology; D005121:Extremities / Q000196:embryology / Q000502:physiology*; D005260:Female; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005697:Galactosides / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006609:High Mobility Group Proteins / Q000378:metabolism; D018398:Homeodomain Proteins; D017403:In Situ Hybridization / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles / Q000378:metabolism; D018878:Limb Buds / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011247:Pregnancy; D000072516:Retinoic Acid 4-Hydroxylase; D055758:SOX9 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000145:classification / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014212:Tretinoin / Q000502:physiology*
C496457:Fgf8 protein, mouse; D005697:Galactosides; D006609:High Mobility Group Proteins; D018398:Homeodomain Proteins; D007211:Indoles; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051524:Fibroblast Growth Factor 8; C088144:HoxA protein; D014212:Tretinoin; D005346:Fibroblast Growth Factors; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse; D001973:Bromodeoxyuridine; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside