Translational control during fetal male germ cell development

描述（由申请人提供）：正常的生殖细胞发育对生殖健康至关重要，也是确保后代健康和预防先天性出生缺陷的关键。目前，人们对胎儿男性生殖细胞中基因表达的调控机制知之甚少。扩大我们对生殖细胞翻译控制的知识将有助于理解导致睾丸发育不良综合征（一系列男性生殖疾病，如原位癌、睾丸癌、隐睾和尿道下裂）近期增加的环境影响，这些疾病起源于生殖细胞发育的胎儿时期。mRNA翻译的控制对胎儿雄性生殖细胞（性腺细胞）发育至关重要。需要特定的RNA结合蛋白来阻断减数分裂起始，并在出生后向精原细胞过渡之前维持卵泡细胞处于静止状态。在此期间介导翻译控制的蛋白质或机制知之甚少。缺乏这种结合蛋白的已知靶mrna阻碍了对翻译控制机制的研究。我们最近在生殖同源盒基因Rhox13中发现了这样一个靶标，Rhox13在胚胎小鼠睾丸的性腺细胞中被转录但未被翻译。胎儿睾丸中的RHOX13蛋白表达受到NANOS2的抑制，而新生儿睾丸中的RHOX13蛋白表达受到视黄酸（RA）的刺激。我们将利用Rhox13和胎儿到新生儿男性生殖细胞的转化作为一个模型系统来确定胎儿睾丸中mrna被抑制的机制，然后在新生儿睾丸中响应RA进入翻译状态。我们的研究结果将显著促进对男性生殖细胞发育过程中翻译抑制和ra调控基因调控的理解。这项工作的结果将指导我们设计全基因组翻译状态阵列分析，以调和胎儿和新生儿睾丸转录组和蛋白质组之间的全球差异。

DESCRIPTION (provided by applicant): Normal germ cell development is critical for reproductive health, as well as to ensure healthy offspring and prevent congenital birth defects. Currently, little is known about how gene expression is regulated in fetal male germ cells. Expanding our knowledge of germ cell translational control will aid in the understanding of environmental influences that contribute to the recent increase in testicular dysgenesis syndrome, a spectrum of male reproductive disorders such as carcinoma in situ, testicular cancer, cryptorchidism, and hypospadia that originate during this fetal period of germ cell development. The control of mRNA translation is essential for fetal male germ cel (gonocyte) development. Specific RNA binding proteins are required to block meiotic initiation and maintain gonocytes in a quiescent state prior to their transition to spermatogonia after birth. Little is known about the proteins or mechanisms that mediate translational control during this period. The lack of known target mRNAs for such binding proteins has impeded the investigation of translational control mechanisms. We have recently identified such a target in the reproductive homeobox gene, Rhox13, which is transcribed but not translated in gonocytes of the fetal mouse testis. RHOX13 protein expression is repressed by NANOS2 in the fetal testis and stimulated by retinoic acid (RA) in the neonatal testis. We will utilize Rhox13 and the fetal to neonatal male germ cel transition as a model system to determine the mechanisms by which mRNAs in the fetal testis are repressed but then move to a translating state in response to RA in the neonatal testis. Our results will significantly advance understanding of translational repression and RA-modulated gene regulation during male germ cell development. Results from this work will guide our design of a genome-wide translational state array analysis to reconcile global differences between the transcriptome and proteome of the fetal and neonatal testis. PUBLIC HEALTH RELEVANCE: Normal germ cell development is critical for reproductive health, as well as to ensure healthy offspring and prevent congenital birth defects. Currently, little is known about how gene expression is regulated in fetal male germ cells. Expanding our knowledge of germ cell translational control will aid in the understanding of environmental influences that contribute to the recent increase in testicular dysgenesis syndrome, a spectrum of male reproductive disorders such as carcinoma in situ, testicular cancer, cryptorchidism, and hypospadia that originate during this fetal period of germ cell development. !