The Role of Retinoic Acid-regulated microRNAs in Spermatogonial Differentiation

描述（由申请人提供）：视黄酸（RA）信号传导对精原细胞分化至关重要。尽管如此，控制精原细胞分化的分子机制仍然知之甚少。虽然有几个小组正在研究RA介导的细胞转录组的变化，在精原细胞分化，RA对基因表达的影响在转录后水平尚未阐明。microRNAs（miRNAs）是一类新的非编码RNA基因，具有序列特异性转录后调节基因表达的功能。miRNAs在精子发生过程中起着重要作用。然而，目前还不清楚是否miRNA可以调节RA信号，从而有助于精原细胞分化。我们的长期目标是确定精原细胞分化中涉及的重要网络。我们的中心假设是，RA调节miRNAs的表达，这些miRNAs反过来又调节编码精原细胞分化蛋白的关键基因的表达。在这个R21应用中，我们建议确定RA调节的miRNA如何潜在地促进精原细胞分化。具体来说，在目标1中，我们假设一个子集的miRNA的表达是由RA信号调节，我们建议确定RA调节的miRNA在精原细胞分化。在目标2中，我们假设RA调节的miRNA调节关键下游蛋白的表达，以增强RA对精原细胞分化的影响，我们建议建立选定的RA调节的miRNA在精原细胞分化中的潜在功能作用。这项研究的完成将有助于确定控制精原细胞分化的调控网络。更好地了解精原细胞分化对男性生殖和避孕具有重要意义。 公共卫生相关性：男性因素不育发生在约10%的男性，虽然精子发生受损的病因很少被确定。视黄酸（RA）对精子发生的第一步--精原细胞分化至关重要。本研究的目的是探索RA靶向microRNA在精原细胞分化调控中的作用，这对维甲酸生物学和男性生殖具有重要意义。

DESCRIPTION (provided by applicant): Retinoic acid (RA) signaling is central to the spermatogonial differentiation. Despite this fact, the molecular mechanisms that govern the spermatogonial differentiation remain poorly understood. While several groups are studying RA-mediated cellular transcriptome changes during spermatogonial differentiation, the effect of RA on gene expression at the posttranscriptional level is yet to be elucidated. MicroRNAs (miRNAs) are a new class of short non-coding RNA genes that function as sequence-specific posttranscriptional regulators of gene expression. It has become apparent that miRNAs play important roles during spermatogenesis. However, it is unclear whether miRNAs can be regulated by RA signaling and could thereby contribute to spermatogonial differentiation. Our long-term goal is to identify the essential networks involved in spermatogonial differentiation. Our central hypothesis is that RA regulates miRNAs expression and these miRNAs in turn modulate expression of key genes encoding protein responsible for spermatogonial differentiation. In this R21 application, we propose to determine how RA-regulated miRNAs potentially contribute to spermatogonial differentiation. Specifically, in Aim 1 we hypothesize that expression of a subset of miRNAs is regulated by RA signaling and we propose to identify the RA-regulated miRNAs during spermatogonial differentiation. In Aim 2 we hypothesize that RA-regulated miRNAs modulate expression of key downstream proteins to enhance the effect of RA on spermatogonia differentiation and we propose to establish the potential functional roles of selected RA-regulated miRNAs in spermatogonial differentiation. Completion of the proposed research will help identify regulatory networks that control spermatogonial differentiation. A better understanding of spermatogonial differentiation has important implications for male reproduction and contraception. PUBLIC HEALTH RELEVANCE: Male factor infertility occurs in about 10% of men, although the etiology of impaired spermatogenesis is rarely identified. Retinoic acid (RA) is critical for spermatogonial differentiation, an initial step of spermatogenesis. The purpose of this proposal is to explore the role of RA-targeted microRNAs in the regulation of spermatogonial differentiation, which has important implications for retinoid biology and male reproduction.