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Developmental regulation of oscillatory expression

振荡表达的发育调节

基本信息

批准号：
10456210
负责人：
Sharon L Amacher
金额：
$ 32.93万
依托单位：
OHIO STATE UNIVERSITY
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：
2015-09-18 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456210
关键词：
3&apos Untranslated Regions Arabidopsis Binding Bioinformatics Biological Pacemakers Biological Process Candidate Disease Gene Cells Cellular biology Clustered Regularly Interspaced Short Palindromic Repeats Development Elements Embryo Embryonic Development Ensure Environment Feedback Fibroblast Growth Factor Gamma Rays Gene Expression Gene Family Genes Genetic Genetic Transcription Hour Human Impairment In Situ Hybridization In Vitro Knock-out Lateral Length Mediating Mesoderm Mesoderm Cell Metabolic Modeling Molecular Molting Mus Mutate Nuclear Pathway interactions Pattern Periodicity Plant Roots Play Poly(A) Tail Post-Transcriptional Regulation Process Proteins RNA Binding Regulation Regulatory Element Reporter Resolution Ribosomes Role Segmentation Clock Pathway Signal Transduction Somites Starvation Stem cell pluripotency System TP53 gene Time Tissue Engineering Tissues Trans-Activators Transcript Transcription Repressor Transgenic Organisms Translating Translational Repression Translations Vertebrates Work Yeasts Zebrafish base biological systems cancer cell cytokine embryonic stem cell experimental study knock-down mutant nerve stem cell notch protein polysome profiling response somitogenesis stem cell biology stem cells transcription factor transcriptome

项目摘要

Project Summary Ultradian oscillatory circuits are pervasive in biological systems. These dynamic oscillators range from pulsatile p53 expression after g-radiation, to periodic nuclear to cytoplasmic shuttling of NFkB transcription factor in response to cytokine, to cyclic expression of Hes/Her transcription factors in stem cells and presomitic mesoderm (PSM). Ultradian genetic oscillators are associated with patterning and developmental transitions – oscillations correlate with yeast metabolic cycles, foreshadow periodic lateral root branching in Arabidopsis, regulate molt cycles in larval worms, associate with stem cell pluripotency, and synchronize transcriptional response to starvation signals in Dictostelium. One biological oscillator is the vertebrate segmentation clock, which controls somitogenesis, the process by which the PSM is sequentially divided into segments called somites. At the core of the segmentation clock is an auto-inhibitory negative feedback loop involving Her/Hes transcriptional repressors, which in turn regulates oscillatory expression of additional ‘cyclic genes’. Although the cyclic genes in human and mouse belong to similar pathways (e.g., Notch, Wnt, FGF, Yap/Hippo), genes in those pathways which are cyclically expressed vary among species, with the Her/Hes gene family genes being common among vertebrates. We study the zebrafish segmentation clock, which oscillates with a 30-minute periodicity and is 4-12 times faster than in mouse or human. In order for a rapid auto-inhibitory oscillator to operate, there must be tight control over synthesis and decay of cyclic gene transcript and protein. A recent experiment in which the Hes7 locus was swapped between human and mouse in vitro PSM systems showed that expression delays and decay, controlled by factors in the host cell environment, are critical regulatory parameters of the clock. To understand the mechanisms regulating these critical parameters, we are using the zebrafish pnrc2 mutant in which transcriptional oscillations occur normally, but post-transcriptional decay mechanisms are disrupted, to identify additional cyclic genes and dissect their regulation. The specific aims of the proposal are to (1) identify Pnrc2-regulated zebrafish embryonic cyclic genes that play critical developmental roles, (2) characterize the regulatory features and factors that control rapid decay dynamics of cyclic gene transcripts, and (3) investigate the role of other post-transcriptional mechanism in regulating segmentation clock function. We anticipate that our work will broadly impact understanding of post- transcriptional mechanisms regulating oscillatory expression in many developmental contexts.

项目总结