Differential gene-expression patterns in genital fibroblasts of normal males and 46,XY females with androgen insensitivity syndrome: evidence for early programming involving the androgen receptor.
Differential gene-expression patterns in genital fibroblasts of normal males and 46,XY females with androgen insensitivity syndrome: evidence for early programming involving the androgen receptor.
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DOI：
10.1186/gb-2003-4-6-r37
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发表时间：
2003
期刊：
影响因子：
12.3
通讯作者：
Brooks JD
中科院分区：
文献类型：
--
作者：
Holterhus PM;Hiort O;Demeter J;Brown PO;Brooks JD
大多数雄激素不敏感综合征 (AIS) 患者携带雄激素受体 (AR) 种系突变，从而干扰或消除其功能。由于生殖器成纤维细胞在体外保留 AR 的表达，因此使用微阵列分析了正常男性和由于已知 AR 突变而具有完全 AIS 的 46,XY 女性的生殖器皮肤成纤维细胞，以深入了解 AR 在人类生殖器分化中的作用。雄激素不敏感综合征 (AIS) 包括从男性不育到完全女性化的一系列表型。大多数 AIS 患者携带雄激素受体 (AR) 种系突变，从而干扰或消除其功能。由于生殖器成纤维细胞在体外保留 AR 的表达，我们使用来自正常男性和由于已知 AR 突变而具有完全 AIS 的 46,XY 女性的生殖器皮肤成纤维细胞，以深入了解 AR 在人类生殖器分化中的作用。使用代表 32,968 个不同基因的 DNA 微阵列，我们鉴定了 404 个转录本，这些转录本在正常个体和受 AIS 影响的个体中培养的生殖器皮肤成纤维细胞之间的转录水平存在显着差异。基因簇分析揭示了参与形态发生关键过程的基因的协调表达。根据动物研究和人类遗传综合征，已知其中一些基因在生殖器分化中具有特定作用。值得注意的是，尽管表达了 AR，但正常和受 AIS 影响的个体的生殖器成纤维细胞均未表现出对二氢睾酮治疗的转录反应。结果表明，除了细胞解剖起源的差异外，产前发育期间的雄激素信号传导有助于在生殖器成纤维细胞中设定持久的、不依赖雄激素的转录程序。我们的研究结果对于理解人类生殖发育中性二态性的建立和稳定性具有广泛的意义。
Most individuals with androgen insensitivity syndrome (AIS) carry germline mutations of the androgen receptor (AR) that interfere with or ablate its function. As genital fibroblasts retain expression of the AR in vitro, genital skin fibroblasts from normal males and 46,XY females with complete AIS due to known AR mutations were analysed using microarrays to gain insights into the role of the AR in human genital differentiation. Androgen insensitivity syndrome (AIS) comprises a range of phenotypes from male infertility to complete feminization. Most individuals with AIS carry germline mutations of the androgen receptor (AR) that interfere with or ablate its function. As genital fibroblasts retain expression of the AR in vitro, we used genital skin fibroblasts from normal males and 46,XY females with complete AIS due to known AR mutations to gain insights into the role of the AR in human genital differentiation. Using DNA microarrays representing 32,968 different genes, we identified 404 transcripts with significant differences in transcription levels between genital skin fibroblasts cultured from normal and AIS-affected individuals. Gene-cluster analyses uncovered coordinated expression of genes involved in key processes of morphogenesis. On the basis of animal studies and human genetic syndromes, several of these genes are known to have specific roles in genital differentiation. Remarkably, genital fibroblasts from both normal and AIS-affected individuals showed no transcriptional response to dihydrotestosterone treatment despite expression of the AR. The results suggest that in addition to differences in the anatomic origin of the cells, androgen signaling during prenatal development contributes to setting long-lasting, androgen-independent transcriptional programs in genital fibroblasts. Our findings have broad implications in understanding the establishment and the stability of sexual dimorphism in human genital development.
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DOI：
10.1016/0022-4731(86)90296-7
发表时间：
1986-07-01
影响因子：
4.1
作者：
CHABAB, A;SULTAN, C;DESCOMPS, B
通讯作者：
DESCOMPS, B
影响因子：
4.1
作者：
Penning, TM;Burczynski, ME;Ratnam, K
通讯作者：
Ratnam, K
影响因子：
5.8
作者：
Holterhus, PM;Bruggenwirth, HT;Brinkmann, AO
通讯作者：
Brinkmann, AO
影响因子：
5.8
作者：
MCPHAUL, MJ;MARCELLI, M;WILSON, JD
通讯作者：
WILSON, JD
影响因子：
10.5
作者：
Kozopas, KM;Samos, CH;Nusse, R
通讯作者：
Nusse, R