TBX1 Regulates Chondrocyte Maturation in the Spheno-occipital Synchondrosis
TBX1 Regulates Chondrocyte Maturation in the Spheno-occipital Synchondrosis
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DOI：
10.1177/0022034520925080
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发表时间：
2020-05-22
影响因子：
7.6
通讯作者：
Yanagisawa, H.
中科院分区：
文献类型：
--
作者：
Funato, N.;Srivastava, D.;Yanagisawa, H.
颅底软骨联合是颅面部的重要生长中心。软骨联合异常会影响邻近区域的发育，包括颅面骨骼。在此，我们报道转录因子TBX1（DiGeorge综合征的候选基因）在中胚层来源的软骨细胞中表达，并通过抑制与软骨细胞肥大和成骨有关的基因的表达，在蝶枕骨联合软骨病的发展中发挥重要且特定的作用。在 Tbx1 缺陷的小鼠中，蝶枕骨联合软骨在出生时就完全矿化。 TBX1 与成骨细胞生成的主分子和软骨细胞成熟的调节因子 RUNX2 相互作用，并抑制其转录活性。事实上，删除 Tbx1 会因加速软骨细胞分化而引发加速矿化，这与蝶枕骨联合软骨病中 RUNX2 下游靶标的异位表达有关。这些发现表明，TBX1 在蝶枕骨联合软骨病发展过程中充当软骨细胞成熟和成骨的调节剂。因此，TBX1对软骨内骨化的严格调节对于蝶枕骨联合软骨细胞分化的正常进展至关重要。
The synchondrosis in the cranial base is an important growth center for the craniofacial region. Abnormalities in the synchondroses affect the development of adjacent regions, including the craniofacial skeleton. Here, we report that the transcription factor TBX1, the candidate gene for DiGeorge syndrome, is expressed in mesoderm-derived chondrocytes and plays an essential and specific role in spheno-occipital synchondrosis development by inhibiting the expression of genes involved in chondrocyte hypertrophy and osteogenesis. In Tbx1-deficient mice, the spheno-occipital synchondrosis was completely mineralized at birth. TBX1 interacts with RUNX2, a master molecule of osteoblastogenesis and a regulator of chondrocyte maturation, and suppresses its transcriptional activity. Indeed, deleting Tbx1 triggers accelerated mineralization due to accelerated chondrocyte differentiation, which is associated with ectopic expression of downstream targets of RUNX2 in the spheno-occipital synchondrosis. These findings reveal that TBX1 acts as a regulator of chondrocyte maturation and osteogenesis during the spheno-occipital synchondrosis development. Thus, the tight regulation of endochondral ossification by TBX1 is crucial for the normal progression of chondrocyte differentiation in the spheno-occipital synchondrosis.