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Dynamic regulatory mechanisms of robust pattern formation in the neural tube

神经管中稳健模式形成的动态调节机制

基本信息

批准号：
10417127
负责人：
SEAN G MEGASON
金额：
$ 33.56万
依托单位：
HARVARD MEDICAL SCHOOL
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：
2015-04-13 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417127
关键词：
Address Adult Animals Back Buffers Cell Separation Cell Shape Cell division Cells Code Complex Computer Models Congenital Abnormality Data Degenerative Disorder Development Developmental Biology Diagnosis Diffuse Disease Dose Dysmorphology Embryo Embryology Equilibrium Evolution Face Feedback Feeds Foundations Funding Gene Dosage Gene Expression Profile Genes Genetic Glean Goals Grant Growth Image Image Analysis Investigation Knowledge Malignant Neoplasms Mechanics Methodology Methods Modeling Molecular Neural Tube Defects Neural tube Noise Operative Surgical Procedures Organ Organism Pattern Pattern Formation Phenotype Positioning Attribute Process Proteins Publishing Quantitative Microscopy Reproducibility Research SHH gene Sea Urchins Shapes Signal Transduction Site Somites Source Specific qualifier value System Testing Time Tissue Engineering Tissues To specify Variant Work Zebrafish base beta catenin biophysical properties cell type course development design egg embryo stage 2 expectation fascinate gene regulatory network insight interest lens mathematical model mechanical pressure morphogens mutant neural patterning notch protein notochord prevent quantitative imaging rational design response

项目摘要

Abstract The long-term goal of our research is to understand the principles that permit developmental systems to robustly construct embryos of the correct pattern, shape, and size. Developmental systems face a gamut of variations from different sources including environmental, genetic, and stochastic, which manifest at multiple levels from molecules to cells to organs. In the face of these challenges, organisms have been designed through evolution to buffer the phenotype against these variations in order to robustly achieve a developmental norm, a process Waddington termed canalization. As our knowledge of the molecular and cellular details of patterning systems has expanded, there is now the opportunity to understand the systems level mechanisms that give rise to robust pattern formation. Here we focus on pattern robustness through the lens of scaling and size control. Scaling is a remarkable process in which the size of a pattern can be adjusted to the available size of the tissue. Scaling has fascinated and baffled embryologists since the time of Hans Driesch who in 1885 found that when the blastomeres of a two-cell stage sea urchin embryo are separated, the result is not two partial embryos but rather two complete embryos in which all their pattern is scaled by half. Similar results have since been found in a variety of organisms, but the surgical manipulations required to generate size- reduced animals are generally difficult and result in a lot of variability, thus limiting quantitative investigation. Recently, we have developed a new method for generating zebrafish eggs of different size that is robust and reproducible. Such embryos have qualitatively normal but scaled patterning and can give rise to viable adults. At a molecular level we find that most gene expression patterns (e.g. morphogens and their targets) scale with the tissues they pattern; however, a small subset of genes, the ones that sense tissue size to regulate scaling (e.g. by interacting with morphogens), do not. Thus, these size altered embryos represent a powerful and unique method to identify and determine the mechanisms of pattern scaling. Ultimately, tissue size is determined by balancing the rates of proliferation and differentiation over the course of development. We have found that the balance of proliferation and differentiation in the neural tube is under negative feedback control by mechanical pressure/tissue packing. Here we will use a combination of quantitative imaging, molecular and mechanical perturbations, and computer modeling to determine the systems-level mechanisms that allow: 1) morphogen patterning to scale to fit the available space, and 2) proliferation and differentiation rates to be balanced to cause a tissue to grow to fit the available space. These questions will be addressed in the zebrafish neural tube, but we expect the resulting mechanisms to be widely applicable. Such an integrated understanding is important for diagnosing and treating birth defects such as neural tube defects and in the rational design of engineered tissues.

摘要

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tetrahedral serial multiview microscopy and image fusion for improved resolution and extent in stained zebrafish embryos.

四面体串行多视图显微镜和图像融合可提高染色斑马鱼胚胎的分辨率和范围。

DOI：
10.1002/dvdy.683
发表时间：
2023
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
0
作者：
Kroll,JohannaB;Cha,Anna;Oyler-Yaniv,Alon;Lambert,Talley;Swinburne,IanA;Murphy,Andrew;Megason,SeanG
通讯作者：
Megason,SeanG

Orientation of Turing-like Patterns by Morphogen Gradients and Tissue Anisotropies.