The primary site of the acrocephalic feature in Apert Syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling.
Activation of osteoblastic bone anabolism in the calvarial sutures is considered to be the essential pathologic condition underlying mutant FGFR2-related craniofacial dysostosis. However, early clinical investigations indicated that abnormal cartilage development in the cranial base was rather a primary site of abnormal feature in Apert Syndrome (AS). To examine the significance of cartilaginous growth of the cranial base in AS, we generated a transgenic mouse bearing AS-type mutant Fgfr2IIIc under the control of the Col2a1 promoter-enhancer (Fgfr2IIIc(P253R) mouse). Despite the lacking expression of Fgfr2IIIc(P253R) in osteoblasts, exclusive disruption of chondrocytic differentiation and growth reproduced AS-like acrocephaly accompanied by short anterior cranial base with fusion of the cranial base synchondroses, maxillary hypoplasia and synostosis of the calvarial sutures with no significant abnormalities in the trunk and extremities. Gene expression analyses demonstrated upregulation of p21, Ihh and Mmp-13 accompanied by modest increase in expression of Sox9 and Runx2, indicating acceleration of chondrocytic maturation and hypertrophy in the cranial base of the Fgfr2IIIc(P253R) mice. Furthermore, an acquired affinity and specificity of mutant FGFR2IIIc(P253R) receptor with FGF2 and FGF10 is suggested as a mechanism of activation of FGFR2 signaling selectively in the cranial base. In this report, we strongly suggest that the acrocephalic feature of AS is not alone a result of the coronal suture synostosis, but is a result of the primary disturbance in growth of the cranial base with precocious endochondral ossification.
Department of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Gakkocho-dori 2-5274, Niigata 951-8514, Japan. nagata@dent.niigata-u.ac.jp
Masaki
M
Nagata
Glen H
GH
Nuckolls
Xibin
X
Wang
Lillian
L
Shum
Yukie
Y
Seki
Tomoyuki
T
Kawase
Katsu
K
Takahashi
Kazuaki
K
Nonaka
Ichiro
I
Takahashi
Arhab A
AA
Noman
Kenji
K
Suzuki
Harold C
HC
Slavkin
D000168:Acrocephalosyndactylia / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D015398:Signal Transduction; D019076:Transgenes
D017931:DNA Primers; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2