Loss of Fgfr2 leads to partial XY sex reversal
Loss of Fgfr2 leads to partial XY sex reversal
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DOI：
10.1016/j.ydbio.2007.11.010
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发表时间：
2008-02-01
影响因子：
2.7
通讯作者：
Harley, Vincent R.
中科院分区：
文献类型：
--
作者：
Bagheri-Fam, Stefan;Sim, Helena;Harley, Vincent R.
在哺乳动物中，性别是由一个平衡的基因作用网络决定的，当改变时会导致性发育障碍（DSD，以前称为间性）。在XY性腺中，当SRY上调SOX 9时，假定的支持细胞开始分化，SOX 9反过来激活FGF 9和PGDS以维持其自身的表达。这项研究确定了一个新的和重要的成分，FGF信号在性别决定。混合129/C57 BL 6遗传背景的Fgfr 2突变XY小鼠具有正常睾丸或发育的卵睾丸，主要是睾丸组织。然而，与C57 BL 6小鼠的回交导致了广泛的性腺表型，从发育不全的睾丸到主要具有卵巢组织的卵睾丸，类似于Fgf 9敲除小鼠。由于典型的雄性特异性FGF 9与体腔上皮的结合在Fgfr 2突变XY性腺中被消除，这些结果表明FGFR 2充当FGF 9的受体。Pgds和S 0X 9在Fgfr 2突变的卵睾丸的睾丸部分内保持表达，表明前列腺素途径独立于FGFR 2起作用以维持S 0X 9表达。我们可以进一步证明，双杂合Fgfr 2/Sox 9基因敲除小鼠的卵睾丸，表明Fgfr 2和Sox 9可以作为修饰中间性基因在杂合状态。总之，我们提供的证据表明FGFR 2对小鼠的雄性性别决定很重要，从而使人FGFR 2成为未解决的DSD病例如10 q26缺失的候选基因。(C)2007爱思唯尔公司All rights reserved.
In mammals, sex is determined in the bipotential embryonic gonad by a balanced network of gene actions which when altered causes disorders of sexual development (DSD, formerly known as intersex). In the XY gonad, presumptive Sertoli cells begin to differentiate when SRY upregulates SOX9, which in turn activates FGF9 and PGDS to maintain its own expression. This study identifies a new and essential component of FGF signaling in sex determination. Fgfr2 mutant XY mice on a mixed 129/C57BL6 genetic background had either normal testes, or developed ovotestes, with predominantly testicular tissue. However, backcrossing to C57BL6 mice resulted in a wide range of gonadal phenotypes, from hypoplastic testes to ovotestes with predominantly ovarian tissue, similar to Fgf9 knockout mice. Since typical male-specific FGF9-binding to the coelomic epithelium was abolished in Fgfr2 mutant XY gonads, these results suggest that FGFR2 acts as the receptor for FGF9. Pgds and SOX9 remained expressed within the testicular portions of Fgfr2 mutant ovotestes, suggesting that the Prostaglandin pathway acts independently of FGFR2 to maintain SOX9 expression. We could further demonstrate that double-heterozygous Fgfr2/Sox9 knockout mice developed ovotestes, demonstrating that both Fgfr2 and Sox9 can act as modifier intersex genes in the heterozygous state. In summary, we provide evidence that FGFR2 is important for male sex determination in mice, thereby rendering human FGFR2 a candidate gene for unsolved DSD cases such as 10q26 deletions. (C) 2007 Elsevier Inc. All rights reserved.