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Dnd1 and repression of transcription in primordial germ cells

Dnd1 和原始生殖细胞转录抑制

基本信息

批准号：
8888237
负责人：
Jing Yang
金额：
$ 30.53万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888237
关键词：
Affect Apoptosis Autophagocytosis Caenorhabditis elegans Cell Count Cell Lineage Cells Complex Couples Defect Development Developmental Biology Embryo Embryonic Development Failure Family Fertilization Fertilization in Vitro Gene Expression Genes Genetic Transcription Germ Germ Cells Gonadal structure Human Infertility Inherited Invertebrates Knowledge Messenger RNA Neurula Oocytes Play Proliferating Proteins RNA-Binding Proteins Recruitment Activity Repression Reproductive Biology Reproductive Health Role Signal Transduction Somatic Cell Specific qualifier value Staging Structure of primordial sex cell Techniques Time Tissues To specify Translation Initiation Translations Xenopus gastrulation gene repression genome-wide member overexpression premature prevent programs protein degradation protein expression public health relevance stem cell biology

项目摘要

DESCRIPTION (provided by applicant): The germline is the only cell lineage capable of giving rise to the gametes. Defective germline development results in reduction or elimination of germ cells and ultimately causes infertility in humans, which affects 10- 15% of couples. Germ cell development begins early during embryonic development. After specification of primordial germ cells (PGCs), transcription is transiently repressed in PGCs. This is in stark contrast to the development of somatic lineages, which often relies on the activation of complex transcriptional programs. The establishment of such a transient genome-wide transcriptionally repressive state is critically important for early stages of the germline development, because it prevents PGCs from responding to surrounding signals that specify somatic cell fates. Failure to repress transcription during early stages of PGC development causes somatic differentiation and apoptosis of PGCs, which eventually leads to elimination of germ cells from the embryo. Understanding how this global transcriptionally repressive state is established in PGCs thus is highly relevant to human reproductive health. Our preliminary studies suggest that Dnd1, a RNA-binding protein required for vertebrate germ cell development, plays an essential role in establishing the genome- wide transcriptionally repressive state in PGCs. We found that Dnd1 protein is rapidly degraded by autophagy, making it intrinsically unstable. During development, Dnd1 is expressed at the right time and in the right place, and is required for the expression of Nanos1, which represses transcription in PGCs. We hypothesize that the genome-wide transcriptionally repressive state in PGCs is established through precisely regulated expression of Dnd1 protein. Specific aims are: Aim 1: To determine if Dnd1 is a central upstream regulator of the transcriptional repression in PGCs. Aim 2: To investigate the mechanisms through which Dnd1 regulates nanos1 translation. Aim 3: To determine whether autophagy- dependent Dnd1 turnover is important for the germline development.