Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid.
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Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid. / Laue, Kathrin; Pogoda, Hans-Martin; Daniel, Philip B; van Haeringen, Arie; Alanay, Yasemin; von Ameln, Simon; Rachwalski, Martin; Morgan, Tim; Gray, Mary J; Breuning, Martijn H; Sawyer, Gregory M; Sutherland-Smith, Andrew J; Nikkels, Peter G; Kubisch, Christian; Bloch, Wilhelm; Wollnik, Bernd; Hammerschmidt, Matthias; Robertson, Stephen P.
In: AM J HUM GENET, Vol. 89, No. 5, 5, 2011, p. 595-606.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid.
AU - Laue, Kathrin
AU - Pogoda, Hans-Martin
AU - Daniel, Philip B
AU - van Haeringen, Arie
AU - Alanay, Yasemin
AU - von Ameln, Simon
AU - Rachwalski, Martin
AU - Morgan, Tim
AU - Gray, Mary J
AU - Breuning, Martijn H
AU - Sawyer, Gregory M
AU - Sutherland-Smith, Andrew J
AU - Nikkels, Peter G
AU - Kubisch, Christian
AU - Bloch, Wilhelm
AU - Wollnik, Bernd
AU - Hammerschmidt, Matthias
AU - Robertson, Stephen P
PY - 2011
Y1 - 2011
N2 - Excess exogenous retinoic acid (RA) has been well documented to have teratogenic effects in the limb and craniofacial skeleton. Malformations that have been observed in this context include craniosynostosis, a common developmental defect of the skull that occurs in 1 in 2500 individuals and results from premature fusion of the cranial sutures. Despite these observations, a physiological role for RA during suture formation has not been demonstrated. Here, we present evidence that genetically based alterations in RA signaling interfere with human development. We have identified human null and hypomorphic mutations in the gene encoding the RA-degrading enzyme CYP26B1 that lead to skeletal and craniofacial anomalies, including fusions of long bones, calvarial bone hypoplasia, and craniosynostosis. Analyses of murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 suggest that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicate that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning. This work reveals a physiological role for RA in partitioning skeletal elements and in the maintenance of cranial suture patency.
AB - Excess exogenous retinoic acid (RA) has been well documented to have teratogenic effects in the limb and craniofacial skeleton. Malformations that have been observed in this context include craniosynostosis, a common developmental defect of the skull that occurs in 1 in 2500 individuals and results from premature fusion of the cranial sutures. Despite these observations, a physiological role for RA during suture formation has not been demonstrated. Here, we present evidence that genetically based alterations in RA signaling interfere with human development. We have identified human null and hypomorphic mutations in the gene encoding the RA-degrading enzyme CYP26B1 that lead to skeletal and craniofacial anomalies, including fusions of long bones, calvarial bone hypoplasia, and craniosynostosis. Analyses of murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 suggest that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicate that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning. This work reveals a physiological role for RA in partitioning skeletal elements and in the maintenance of cranial suture patency.
KW - Animals
KW - Humans
KW - Female
KW - Disease Models, Animal
KW - Mice
KW - Gene Expression Regulation, Developmental
KW - Sequence Homology, Amino Acid
KW - Cell Differentiation
KW - Pregnancy
KW - Osteogenesis/drug effects/genetics
KW - Polymorphism, Genetic/genetics
KW - Cranial Sutures/drug effects/embryology/growth & development/pathology
KW - Craniosynostoses/enzymology/genetics/pathology
KW - Cytochrome P-450 Enzyme System/antagonists & inhibitors/genetics
KW - Fetal Death/genetics
KW - Growth and Development/genetics
KW - Osteoblasts/cytology
KW - Tretinoin/metabolism/pharmacology
KW - Zebrafish/embryology/genetics
KW - Zebrafish Proteins/genetics
KW - Animals
KW - Humans
KW - Female
KW - Disease Models, Animal
KW - Mice
KW - Gene Expression Regulation, Developmental
KW - Sequence Homology, Amino Acid
KW - Cell Differentiation
KW - Pregnancy
KW - Osteogenesis/drug effects/genetics
KW - Polymorphism, Genetic/genetics
KW - Cranial Sutures/drug effects/embryology/growth & development/pathology
KW - Craniosynostoses/enzymology/genetics/pathology
KW - Cytochrome P-450 Enzyme System/antagonists & inhibitors/genetics
KW - Fetal Death/genetics
KW - Growth and Development/genetics
KW - Osteoblasts/cytology
KW - Tretinoin/metabolism/pharmacology
KW - Zebrafish/embryology/genetics
KW - Zebrafish Proteins/genetics
M3 - SCORING: Journal article
VL - 89
SP - 595
EP - 606
JO - AM J HUM GENET
JF - AM J HUM GENET
SN - 0002-9297
IS - 5
M1 - 5
ER -
