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，关于基因表达在胎儿男性生殖细胞中是如何调节的知之甚少。扩大我们的生殖细胞翻译控制的知识将有助于理解环境的影响，有助于最近增加睾丸发育不全综合征，一系列的男性生殖疾病，如原位癌，睾丸癌，隐睾症，尿道下裂，起源于这个胎儿时期的生殖细胞发育。 mRNA翻译的调控对男性生殖细胞的发育至关重要。需要特异性RNA结合蛋白来阻断减数分裂起始，并在出生后生殖母细胞转变为精原细胞之前维持其处于静止状态。在此期间，对介导翻译控制的蛋白质或机制知之甚少。缺乏已知的目标mRNA的结合蛋白，阻碍了翻译控制机制的调查。我们最近已经确定了这样一个目标，在生殖同源异型盒基因，Rhox13，这是转录，但不翻译的胚胎小鼠睾丸的生殖细胞。RHOX13蛋白表达在胎儿睾丸中被NANOS2抑制，在新生儿睾丸中被视黄酸（RA）刺激。我们将利用Rhox13和胎儿到新生儿男性生殖细胞的转换作为一个模型系统，以确定胎儿睾丸中的mRNA被抑制，但随后移动到一个翻译状态，以响应RA在新生儿睾丸的机制。我们的研究结果将显着推进理解翻译抑制和RA调制的基因调控在男性生殖细胞的发展。这项工作的结果将指导我们设计一个全基因组翻译状态阵列分析，以协调胎儿和新生儿睾丸的转录组和蛋白质组之间的全球差异。 公共卫生相关性：正常的生殖细胞发育对于生殖健康以及确保健康的后代和预防先天性出生缺陷至关重要。目前，关于基因表达在胎儿男性生殖细胞中是如何调节的知之甚少。扩大我们的生殖细胞翻译控制的知识将有助于理解环境的影响，有助于最近增加睾丸发育不全综合征，一系列的男性生殖疾病，如原位癌，睾丸癌，隐睾症，尿道下裂，起源于这个胎儿时期的生殖细胞发育。 !

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. !