Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid.
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.
Institute of Developmental Biology, University of Cologne, D-50674 Cologne, Germany.
Kathrin
K
Laue
Hans-Martin
HM
Pogoda
Philip B
PB
Daniel
Arie
A
van Haeringen
Yasemin
Y
Alanay
Simon
S
von Ameln
Martin
M
Rachwalski
Tim
T
Morgan
Mary J
MJ
Gray
Martijn H
MH
Breuning
Gregory M
GM
Sawyer
Andrew J
AJ
Sutherland-Smith
Peter G
PG
Nikkels
Christian
C
Kubisch
Wilhelm
W
Bloch
Bernd
B
Wollnik
Matthias
M
Hammerschmidt
Stephen P
SP
Robertson
D000818:Animals; D002454:Cell Differentiation; D003393:Cranial Sutures / Q000187:drug effects / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D003398:Craniosynostoses / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005313:Fetal Death / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D048788:Growth and Development / Q000235:genetics; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011247:Pregnancy; D000072516:Retinoic Acid 4-Hydroxylase; D017386:Sequence Homology, Amino Acid; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics*
D065607:Cytochrome P-450 Enzyme Inhibitors; D029961:Zebrafish Proteins; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase