NRG1 and KITL Signal Downstream of Retinoic Acid in the Germline to Support Soma-Free Syncytial Growth of Differentiating Spermatogonia.
NRG1 and KITL Signal Downstream of Retinoic Acid in the Germline to Support Soma-Free Syncytial Growth of Differentiating Spermatogonia.
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DOI：
10.1038/cddiscovery.2015.18
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发表时间：
2015
影响因子：
7
通讯作者：
Hamra FK
中科院分区：
文献类型：
--
作者：
Chapman KM;Medrano GA;Chaudhary J;Hamra FK
明确的支持精原细胞分化的培养系统将为研究精子发生提供实验平台。然而，不需要体细胞就足以支持精原细胞分化的生殖系固有信号机制在很大程度上仍然不清楚。在这里，我们分析了大鼠睾丸细胞中EGF超家族受体和配体的多样性，并描述了通过ERBB3共转导蛋白ERBB2的生殖系内源信号是维甲酸通过分化精原细胞诱导合胞生长所必需的。与ERBB2/3激动剂NRG1类似，我们发现KIT配体(KITL)在没有血清或体细胞的情况下有力地支持精原细胞分化。ERBB2抑制剂不能阻断KITL依赖的精原细胞的发育，KITL在分化时阻止ERBB3缺陷的精原细胞退化。因此，我们报道了NRG1和KITL在生殖系中激活维甲酸信号下游的替代通路，这些通路对于干细胞在培养中经历精子发生的减数分裂前步骤是必不可少的。强劲的血清/无胞体精原分化为在培养中研究哺乳动物生殖细胞生物学和发现能够在体外推动减数分裂进展的因素打开了新的大门。
Defined culture systems supporting spermatogonial differentiation will provide experimental platforms to study spermatogenesis. However, germline-intrinsic signaling mechanisms sufficient to support spermatogonial differentiation without somatic cells remain largely undefined. Here we analyzed EGF superfamily receptor and ligand diversity in rat testis cells and delineated germline-intrinsic signaling via an ERBB3 co-transducer, ERBB2, as essential for retinoic acid-induced syncytial growth by differentiating spermatogonia. Similar to the ERBB2/3 agonist NRG1, we found that KIT Ligand (KITL) robustly supported spermatogonial differentiation without serum or somatic cells. ERBB2 inhibitors failed to disrupt KITL-dependent spermatogonial development, and KITL prevented ERBB3-deficient spermatogonial degeneration upon differentiation. Thus we report that NRG1 and KITL activate alternative pathways downstream of retinoic acid signaling in the germline that are essential for stem cells to undergo premeiotic steps of spermatogenesis in culture. Robust serum/soma-free spermatogonial differentiation opens new doors to study mammalian germ cell biology in culture and to discover factors that can drive meiotic progression in vitro.