TY - JOUR
T1 - Mesodermal expression of Fgfr2S252W is necessary and sufficient to induce craniosynostosis in a mouse model of Apert syndrome
AU - Holmes, Greg
AU - Basilico, Claudio
N1 - Funding Information:
The authors thank Dr Ethylin Wang Jabs for critical reading of the manuscript. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant Number AR051358 ). Technical assistance was provided by the NYULMC Histopathology Core ( NYU Cancer Institute Center Support Grant 5P30CA0016087 ).
PY - 2012/8/15
Y1 - 2012/8/15
N2 - Coordinated growth of the skull and brain are vital to normal human development. Craniosynostosis, the premature fusion of the calvarial bones of the skull, is a relatively common pediatric disease, occurring in 1 in 2500 births, and requires significant surgical management, especially in syndromic cases. Syndromic craniosynostosis is caused by a variety of genetic lesions, most commonly by activating mutations of FGFRs 1-3, and inactivating mutations of TWIST1. In a mouse model of TWIST1 haploinsufficiency, cell mixing between the neural crest-derived frontal bone and mesoderm-derived parietal bone accompanies coronal suture fusion during embryonic development. However, the relevance of lineage mixing in craniosynostosis induced by activating FGFR mutations is unknown. Here, we demonstrate a novel mechanism of suture fusion in the Apert Fgfr2S252W mouse model. Using Cre/lox recombination we simultaneously induce expression of Fgfr2S252W and Β-galactosidase in either the neural crest or mesoderm of the skull. We show that mutation of the mesoderm alone is necessary and sufficient to cause craniosynostosis, while mutation of the neural crest is neither. The lineage border is not disrupted by aberrant cell migration during fusion. Instead, the suture mesenchyme itself remains intact and is induced to undergo osteogenesis. We eliminate postulated roles for dura mater or skull base changes in craniosynostosis. The viability of conditionally mutant mice also allows post-natal assessment of other aspects of Apert syndrome.
AB - Coordinated growth of the skull and brain are vital to normal human development. Craniosynostosis, the premature fusion of the calvarial bones of the skull, is a relatively common pediatric disease, occurring in 1 in 2500 births, and requires significant surgical management, especially in syndromic cases. Syndromic craniosynostosis is caused by a variety of genetic lesions, most commonly by activating mutations of FGFRs 1-3, and inactivating mutations of TWIST1. In a mouse model of TWIST1 haploinsufficiency, cell mixing between the neural crest-derived frontal bone and mesoderm-derived parietal bone accompanies coronal suture fusion during embryonic development. However, the relevance of lineage mixing in craniosynostosis induced by activating FGFR mutations is unknown. Here, we demonstrate a novel mechanism of suture fusion in the Apert Fgfr2S252W mouse model. Using Cre/lox recombination we simultaneously induce expression of Fgfr2S252W and Β-galactosidase in either the neural crest or mesoderm of the skull. We show that mutation of the mesoderm alone is necessary and sufficient to cause craniosynostosis, while mutation of the neural crest is neither. The lineage border is not disrupted by aberrant cell migration during fusion. Instead, the suture mesenchyme itself remains intact and is induced to undergo osteogenesis. We eliminate postulated roles for dura mater or skull base changes in craniosynostosis. The viability of conditionally mutant mice also allows post-natal assessment of other aspects of Apert syndrome.
KW - Apert syndrome
KW - Craniosynostosis
KW - Mesoderm
KW - Neural crest
UR - http://www.scopus.com/inward/record.url?scp=84864027660&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2012.05.026
DO - 10.1016/j.ydbio.2012.05.026
M3 - Article
C2 - 22664175
AN - SCOPUS:84864027660
SN - 0012-1606
VL - 368
SP - 283
EP - 293
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -