Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor.
Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor.
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DOI：
10.1371/journal.pgen.1005501
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发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Ghyselinck NB
中科院分区：
文献类型：
--
作者：
Gely-Pernot A;Raverdeau M;Teletin M;Vernet N;Féret B;Klopfenstein M;Dennefeld C;Davidson I;Benoit G;Mark M;Ghyselinck NB
全反式维甲酸（ATRA）是促进男性生殖细胞分化的重要物质，但其作用机制尚不清楚。为了解决这个问题，我们分析了小鼠的表型缺乏，在精原细胞，所有rexinoid受体（RXRA，RXRB和RXRG）或所有ATRA受体（RARA，RARB和RARG）。我们证明，在精原细胞中RXRA和RXRB的联合消融概括了在精原细胞中RAR消融后观察到的一组缺陷。我们还表明，全反式维甲酸激活RAR和RXR结合到一个保守的调节区，以增加表达的SALL 4A转录因子在精原细胞。我们的研究结果表明，这个主要的多能性基因是一个目标的ATRA信号和RAR/RXR异二聚体的功能单位驱动其在精原细胞中的表达。它们增加了ATRA促进KIT酪氨酸激酶受体表达的机制，从而触发精原细胞分化的关键步骤。重要的是，它们还表明减数分裂最终在生殖细胞内不存在RAR/RXR途径的情况下发生，并表明指导该过程是不依赖于ATRA的，或者需要来自支持细胞的ATRA信号。从未成熟的生殖细胞（称为精原细胞）分化精子关键地依赖于视黄酸（ATRA），视黄酸是维生素A的活性代谢物，其通过与称为RXR和RAR的核受体结合而起作用。为了了解ATRA控制生殖细胞分化的机制，我们产生了同时缺乏所有RXR或所有RAR的精原细胞特异性小鼠。从他们的表型分析，我们表明，减数分裂不需要RAR/RXR依赖的途径在生殖细胞，并提出这一过程是ATRA独立或需要ATRA信号起源于体细胞。我们还表明，RXR，在与RAR的二聚体的形式，可以驱动精原细胞分化，通过结合到位于Sall 4基因的调控区。这一发现是重要的，因为已知由Sall 4编码的转录因子调节KIT的表达，KIT是一种关键的酪氨酸激酶受体，在睾丸癌中经常被解除调节。
All-trans retinoic acid (ATRA) is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG) or all ATRA receptors (RARA, RARB and RARG). We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells. Differentiation of spermatozoa from immature germ cells, called spermatogonia, critically depends on retinoic acid (ATRA), the active metabolite of vitamin A that acts though binding to nuclear receptors called RXR and RAR. To understand the mechanism by which ATRA control germ cell differentiation, we generated mice simultaneously lacking all RXR or all RAR specifically in spermatogonia. From their phenotypic analysis, we demonstrate that meiosis does not require a RAR/RXR-dependent pathway in germ cells and propose that this process is either ATRA-independent or requires an ATRA signal originating from somatic cells. We also show that RXR, in the form of dimers with RAR, can drive spermatogonia differentiation through binding to a regulatory region located in the Sall4 gene. This finding is significant, as the transcription factor encoded by Sall4 is known to regulate the expression of KIT, a key tyrosine kinase receptor which is frequently deregulated in testicular cancer.