Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development.
Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development.
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DOI：
10.1371/journal.pone.0054606
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Western PS
中科院分区：
文献类型：
--
作者：
Miles DC;Wakeling SI;Stringer JM;van den Bergen JA;Wilhelm D;Sinclair AH;Western PS
发育中的睾丸提供了一个滋养生殖细胞发育的环境，最终确保精子发生和生育能力。对这种环境的影响被认为是异常生殖细胞发育和生殖细胞肿瘤前体形成的基础。睾丸形成和男性胎儿生殖细胞发育中的信号事件在很大程度上仍然未知。对缺乏单个TGFβ家族成员的基因敲除小鼠的分析表明，TGFβ不是性别决定所必需的。然而，由于功能冗余，可能这些配体在性腺发育中的其他功能仍有待发现。使用FACS纯化的性腺细胞，在这项研究中，我们表明编码激活素、TGFβ、Nodal及其各自受体的基因以性别和细胞类型特异性模式表达，表明在睾丸和生殖细胞发育中的特殊作用。通过受体ALK 4、ALK 5和ALK 7以及单独的ALK 5抑制信号传导，证明了在关键睾丸决定期期间睾丸索形成需要TGFβ信号传导。我们还表明，通过激活素/NODAL受体，ALK 4和ALK 7的信号传导是促进雄性生殖细胞分化和进入有丝分裂停滞所必需的。最后，我们的数据表明，Nodal在雄性生殖细胞中特异性表达，并且当通过ALK 4/5/7的信号传导被阻断时，关键多能性基因Nanog的表达显著降低。我们抑制多种激活素/NODAL/TGFβ受体的策略减少了这些信号传导途径之间的功能冗余，从而揭示了TGFβ和激活素信号传导在睾丸形成和雄性生殖细胞发育过程中的新的重要作用。
The developing testis provides an environment that nurtures germ cell development, ultimately ensuring spermatogenesis and fertility. Impacts on this environment are considered to underlie aberrant germ cell development and formation of germ cell tumour precursors. The signaling events involved in testis formation and male fetal germ cell development remain largely unknown. Analysis of knockout mice lacking single Tgfβ family members has indicated that Tgfβ's are not required for sex determination. However, due to functional redundancy, it is possible that additional functions for these ligands in gonad development remain to be discovered. Using FACS purified gonadal cells, in this study we show that the genes encoding Activin's, TGFβ's, Nodal and their respective receptors, are expressed in sex and cell type specific patterns suggesting particular roles in testis and germ cell development. Inhibition of signaling through the receptors ALK4, ALK5 and ALK7, and ALK5 alone, demonstrated that TGFβ signaling is required for testis cord formation during the critical testis-determining period. We also show that signaling through the Activin/NODAL receptors, ALK4 and ALK7 is required for promoting differentiation of male germ cells and their entry into mitotic arrest. Finally, our data demonstrate that Nodal is specifically expressed in male germ cells and expression of the key pluripotency gene, Nanog was significantly reduced when signaling through ALK4/5/7 was blocked. Our strategy of inhibiting multiple Activin/NODAL/TGFβ receptors reduces the functional redundancy between these signaling pathways, thereby revealing new and essential roles for TGFβ and Activin signaling during testis formation and male germ cell development.
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影响因子：
--
作者：
Garcia-Ortiz JE;Pelosi E;Omari S;Nedorezov T;Piao Y;Karmazin J;Uda M;Cao A;Cole SW;Forabosco A;Schlessinger D;Ottolenghi C
通讯作者：
Ottolenghi C
影响因子：
3.6
作者：
Byfield, SD;Major, C;Roberts, AB
通讯作者：
Roberts, AB
DOI：
10.1073/pnas.0702581104
发表时间：
2007-10-16
影响因子：
11.1
作者：
Kim, Yuna;Bingham, Nathan;Capel, Blanche
通讯作者：
Capel, Blanche
影响因子：
4
作者：
Barrios, Florencia;Filipponi, Doria;Dolci, Susanna
通讯作者：
Dolci, Susanna
影响因子：
3.5
作者：
Chassot, Anne-Amandine;Ranc, Fariba;Chaboissier, Marie-Christine
通讯作者：
Chaboissier, Marie-Christine