Dimerization of SOX9 is required for chondrogenesis, but not for sex determination
Dimerization of SOX9 is required for chondrogenesis, but not for sex determination
复制标题
DOI：
10.1093/hmg/ddg182
复制
发表时间：
2003-07-15
影响因子：
3.5
通讯作者：
Vilain, E
中科院分区：
文献类型：
--
作者：
Bernard, P;Tang, PY;Vilain, E
SRY相关的SOX 9基因参与软骨形成和哺乳动物性别决定的早期步骤。人类SOX9基因的突变会导致肢端发育不良，这是一种严重的骨骼畸形综合征，与大多数（但不是所有）XY个体的男性到女性的性别逆转有关。在这里，我们表明，SOX 9包含一个二聚化结构域，并结合合作的DNA增强子元件参与软骨细胞分化的基因，如Col11a2和Col9a2的存在下，作为一个二聚体，但结合作为一个单体的性别决定基因SF1的调控区。移码突变缩短了SOX 9的两个激活结构域，而迄今报道的所有错义突变都位于高迁移率族（HMG）DNA结合结构域。我们确定了一个错义突变（A76E），第一个以外的HMG域，在XY患者表现为campomelic发育不良，但没有性逆转。这种突变破坏了SOX 9的二聚化能力，干扰了DNA结合和随后的Col11a2和Col9a2增强子的反式激活。与患者的表型一致，A76E突变不影响DNA结合和SF1增强子的激活。DNA依赖的合作二聚体可能代表了一种新的机制，以实现组织特异性的基因表达调控的SOX转录因子。这些结果表明，SOX 9合作二聚化是软骨形成所需的，但不是性别决定，并可能解释为什么Campomelic发育不良不需要与XY性逆转。
The SRY-related SOX9 gene is involved in both chondrogenesis and the early steps of mammalian sex determination. Mutations in the human SOX9 gene cause campomelic dysplasia, a severe skeletal malformation syndrome associated with male-to-female sex reversal in most, but not all, XY individuals. Here we show that SOX9 contains a dimerization domain, and binds co-operatively as a dimer in the presence of the DNA enhancer element in genes involved in chondrocyte differentiation, such as Col11a2 and Col9a2, but binds as a monomer to the regulatory region of the sex-determining gene SF1. Frameshift SOX9 mutations truncate its two activation domains, while all missense mutations reported to date lie in the high mobility group (HMG) DNA-binding domain. We identify a missense mutation (A76E), the first outside the HMG domain, in an XY patient presenting with campomelic dysplasia but without sex reversal. This mutation disrupts the dimerization capability of SOX9, interfering with both the DNA binding and consequent transactivation of both the Col11a2 and Col9a2 enhancers. Consistent with the patient's phenotype, the A76E mutation does not affect DNA binding and activation of the SF1 enhancer. DNA-dependent cooperative dimerization could represent a novel mechanism to achieve tissue-specific regulation of gene expression by a SOX transcription factor. These results establish that SOX9 cooperative dimerization is required for chondrogenesis but not for sex determination and may explain why campomelic dysplasia need not be associated with XY sex reversal.