PDF(Pubmed)
Abstract：
Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail. Thus, the aim of this study was to examine the consequences of dysregulating the WNT/β-catenin signalling pathway in the supporting cell lineage during sex-specific human fetal gonad development using an established and extensively validated ex vivo culture model. Inhibition of WNT/β-catenin signalling in human fetal ovary cultures resulted in only minor effects, including reduced secretion of RSPO1 and reduced cell proliferation although this was not consistently found in all treatment groups. In contrast, promotion of WNT/β-catenin signalling in testes severely affected development and function. This included disrupted seminiferous cord structures, reduced cell proliferation, reduced expression of SOX9/AMH, reduced secretion of Inhibin B and AMH as well as loss of the germ cell population. Additionally, Leydig cell function was markedly impaired with reduced secretion of testosterone, androstenedione and INSL3. Together, this study suggests that dysregulated WNT/β-catenin signalling during human fetal gonad development severely impairs testicular development and function. Importantly, our study highlights the notion that sufficient inhibition of the opposite pathway during sex-specific gonadal differentiation is essential to ensure normal development and function also applies to human fetal gonads.
摘要：
性别特异性性腺分化由复杂的信号传导指导，促进男性或女性方向的发育。同时抑制相反的途径。在老鼠身上,WNT/β-catenin通路促进卵巢发育,积极抑制该通路以确保睾丸正常发育的重要性已得到认可.然而,尚未详细研究人类胎儿性腺发育过程中紧密调节的WNT/β-catenin信号传导的改变的含义。因此，这项研究的目的是使用已建立并经过广泛验证的离体培养模型,研究性别特异性人类胎儿性腺发育过程中支持细胞谱系中WNT/β-catenin信号通路失调的后果.在人胎儿卵巢培养物中抑制WNT/β-catenin信号仅产生较小的影响。包括RSPO1分泌减少和细胞增殖减少,但并非在所有治疗组中都一致发现.相比之下,在睾丸中促进WNT/β-catenin信号传导严重影响发育和功能。这包括分裂的产精索结构，减少细胞增殖，SOX9/AMH的表达降低，抑制素B和AMH的分泌减少以及生殖细胞群的损失。此外,睾丸激素分泌减少，睾丸间质细胞功能明显受损，雄烯二酮和INSL3。一起,这项研究表明，人胎儿性腺发育过程中WNT/β-catenin信号传导失调严重损害睾丸发育和功能。重要的是,我们的研究强调了在性别特异性性腺分化过程中对相反途径的充分抑制对于确保正常发育和功能至关重要,也适用于人类胎儿性腺.
