Translational control during fetal male germ cell development

胎儿男性生殖细胞发育过程中的翻译控制

• 批准号: 8287403
• 负责人: Christopher Bennett Geyer
• 金额: $ 43.28万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-07 至 2015-11-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287403
• 关键词: Binding Proteins; Biological Assay; Biological Models; Birth; Carcinoma in Situ; Cell Differentiation process; Cellular Assay; Complex; Congenital Abnormality; Cryptorchidism; Data; Development; Disease; Ensure; Event; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Translation; Germ; Germ Cells; Homeobox Genes; Housekeeping; Investigation; Knowledge; Laboratories; Lead; Malignant neoplasm of testis; Mediating; Meiosis; Messenger RNA; Molecular; Mus; Neonatal; Peptide Initiation Factors; Polyribosomes; Positioning Attribute; Postpartum Period; Proteins; Proteome; RNA; RNA-Binding Proteins; Regulation; Repression; Reproductive Health; Research; Ribonucleoproteins; Ribosomes; Sedimentation process; Signal Transduction; Spermatogonia; Staging; Sucrose; Testicular Dysgenesis Syndrome; Testing; Testis; Translating; Translation Initiation; Translational Repression; Translations; Tretinoin; Vitamin A; Work; derepression; design; fetal; gain of function; genome-wide; insight; male; messenger ribonucleoprotein; offspring; prepuberty; prevent; protein distribution; protein expression; reproductive; response; translation factor

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. !

描述（由申请人提供）：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，人们对胎儿男性生殖细胞中基因表达的调节机制知之甚少。扩大我们对生殖细胞翻译控制的了解将有助于了解导致睾丸发育不全综合征最近增加的环境影响，睾丸发育不全综合征是一系列男性生殖疾病，如原位癌、睾丸癌、隐睾和尿道下裂，均起源于这一时期。生殖细胞发育的胎儿期。 mRNA 翻译的控制对于胎儿男性生殖细胞（生殖母细胞）的发育至关重要。需要特定的RNA结合蛋白来阻止减数分裂的启动并在生殖细胞出生后转变为精原细胞之前将其维持在静止状态。关于这一时期介导翻译控制的蛋白质或机制知之甚少。由于缺乏此类结合蛋白的已知靶标 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，该基因在小鼠胎儿睾丸的性母细胞中转录但不翻译。 RHOX13 蛋白的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变作为模型系统，以确定胎儿睾丸中的 mRNA 被抑制但随后响应新生儿睾丸中的 RA 而转变为翻译状态的机制。我们的结果将显着促进对雄性生殖细胞发育过程中翻译抑制和 RA 调节基因调控的理解。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，以协调胎儿和新生儿睾丸转录组和蛋白质组之间的整体差异。 公共健康相关性：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，人们对胎儿男性生殖细胞中基因表达的调节机制知之甚少。扩大我们对生殖细胞翻译控制的了解将有助于了解导致睾丸发育不全综合征最近增加的环境影响，睾丸发育不全综合征是一系列男性生殖疾病，如原位癌、睾丸癌、隐睾和尿道下裂，均起源于这一时期。生殖细胞发育的胎儿期。 ！