Spatiotemporal disorder in the axial skeleton development of the Mesp2-null mouse: a model of spondylocostal dysostosis and spondylothoracic dysostosis.-猫眼课题宝

DOI：

10.1016/j.bone.2012.11.033

发表时间：

2013-03

期刊：

Bone

影响因子：

4.1

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

Y. Makino;Yu Takahashi;R. Tanabe;Y. Tamamura;Takashi Watanabe;M. Haraikawa;M. Hamagaki;K. Hata;J. Kanno;T. Yoneda;Y. Saga;M. Goseki‐Sone;K. Kaneko;A. Yamaguchi;T. Iimura

脊椎肋骨发育不全（SCDO）是一种遗传性疾病的特点是严重畸形的中轴骨骼。Mesp 2编码一个基本的螺旋-环-螺旋型转录因子，它是体节形成所必需的。它的人类同源基因Mesp 2是一种在SCDO和相关脊椎疾病脊柱胸骨发育不全（STDO）患者中受影响的基因。本研究探讨了Mesp 2基因的缺失如何影响中轴骨的发育，并导致SCDO和STDO的临床特征。我们首先通过三维计算机断层扫描证实，Mesp 2缺失小鼠表现出类似SCDO和STDO的放射学特征的矿化组织图案。组织学观察和细胞外基质分子的原位杂交探测表明，在Mesp 2基因敲除小鼠的发展中的椎体广泛融合的椎间组织的罕见插入。出乎意料的是，椎间组织大多在脊柱中纵向融合，而不是表现出延伸的形成，如基于Mesp 2缺失体节衍生物的尾状化性质所预期的。此外，Mesp 2基因敲除小鼠椎体软骨细胞的分化在空间上是无序的，并且在很大程度上延迟，细胞增殖率增加。磷酸化-Smad 2和-Smad 1/5/8的定量三维免疫荧光图像分析显示，这些软骨形成表型与Mesp 2缺失软骨细胞中TGF-β和BMP信号的空间无序输入相关，并且还显示了具有不同性质的细胞的无定形排列。此外，通过外周定量计算机断层扫描观察到Mesp 2缺失椎骨的骨化显著延迟。目前对Mesp 2基因敲除小鼠脊椎器官发生的时空障碍的观察进一步深入了解了SCDO和STDO的发病机制以及中轴骨骼的生理发育。

Spondylocostal dysostosis (SCDO) is a genetic disorder characterized by severe malformation of the axial skeleton. Mesp2 encodes a basic helix–loop–helix type transcription factor that is required for somite formation. Its human homologue, Mesp2, is a gene affected in patients with SCDO and a related vertebral disorder, spondylothoracic dysostosis (STDO). This work investigated how the loss of Mesp2 affects axial skeleton development and causes the clinical features of SCDO and STDO. We first confirmed, by three-dimensional computed tomography scanning, that Mesp2-null mice exhibited mineralized tissue patterning resembling the radiological features of SCDO and STDO. Histological observations and in situ hybridization probing for extracellular matrix molecules demonstrated that the developing vertebral bodies in Mesp2-null mice were extensively fused with rare insertions of intervertebral tissue. Unexpectedly, the intervertebral tissues were mostly fused longitudinally in the vertebral column, instead of exhibiting extended formation, as was expected based on the caudalized properties of Mesp2-null somite derivatives. Furthermore, the differentiation of vertebral body chondrocytes in Mesp2-null mice was spatially disordered and largely delayed, with an increased cell proliferation rate. The quantitative three-dimensional immunofluorescence image analyses of phospho-Smad2 and -Smad1/5/8 revealed that these chondrogenic phenotypes were associated with spatially disordered inputs of TGF-β and BMP signaling in the Mesp2-null chondrocytes, and also demonstrated an amorphous arrangement of cells with distinct properties. Furthermore, a significant delay in ossification in Mesp2-null vertebrae was observed by peripheral quantitative computed tomography. The current observations of the spatiotemporal disorder of vertebral organogenesis in the Mesp2-null mice provide further insight into the pathogenesis of SCDO and STDO, and the physiological development of the axial skeleton.

Spatiotemporal disorder in the axial skeleton development of the Mesp2-null mouse: a model of spondylocostal dysostosis and spondylothoracic dysostosis.

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