Principles of Robust Developmental Patterning

描述（由申请人提供）：形态发生梯度被广泛用于为细胞提供创建基因表达空间模式所需的位置信息。这种模式的形成在很大程度上是发育形态发生的基础，其准确性和可重复性是值得注意的。事实上，人类出生缺陷的很大一部分是模式形成中相对较小的破坏的直接结果。在大多数情况下，形态梯度的形成以及细胞对它们的反应受到相互作用的转录因子、受体和共受体网络的复杂调节。很有可能，这种调节进化使空间模式对生物学相关的扰动（遗传变异、环境不确定性、内在随机性等）具有鲁棒性。我们将重点关注果蝇翅膀成像盘前后轴的BMP梯度，通过将实验生物学与数学建模和分析紧密结合的合作方法，探索和阐明稳健模式的机制基础。研究将涉及三个相关领域：首先，我们将量化细胞间的可变性，这种可变性通常会阻碍组织在浅形态梯度下产生基因表达的清晰边界，并研究这种“空间噪声”如何在控制翼静脉图案的基因调控网络的不同阶段发生变化。其次，我们将继续研究最近的证据，表明图案不仅对坡度中的形态素水平敏感，而且对局部坡度斜率也敏感。作为这项工作的一部分，我们将测试坡度检测是由脂肪信号通路介导的假设，并服务于减少空间噪声的目的。第三，我们将扩展先前形态梯度形成和解释的数学模型，以阐明作为实现相对于个体类型扰动的鲁棒性策略的调节机制之间出现的权衡。特别是，这样的模型将包含迄今为止尚未进行数学分析的机制和性能目标。总的来说，这项工作的目标是提供一个更连贯的理解，如何利用空间动态生物系统的复杂调节来实现各种条件下的稳健性能。最终，这些结果将有助于我们了解导致结构性出生缺陷和其他发育异常的病理过程。)

DESCRIPTION (provided by applicant): Morphogen gradients are widely used to provide cells with the positional information needed to create spatial patterns of gene expression. Such pattern formation underlies a great deal of developmental morphogenesis, and is notable for its accuracy and reproducibility. Indeed, a large fraction of human birth defects are the direct result of relatively small disruptions in pattern formation. In most cases, the formation of morphogen gradients, and the responses of cells to them, is subject to complex regulation by networks of interacting transcription factors, receptors, and co-receptors. It is likely that such regulation evolved to make spatial patterning robust to biologically relevant perturbations (genetic variability, environmental uncertainty, intrinsic stochasticity, etc.). Focusing on the BMP gradient that patterns the antero-posterior axis of the Drosophila wing imaginal disc, we will explore and elucidate the mechanistic basis for robust patterning, through a collaborative approach that closely intertwines experimental biology with mathematical modeling and analysis. Three related areas of investigation will be pursued: First, we will quantify the cell-to-cell variability that normally impedes the ability of tissues to generate sharp borders of gene expression in response to shallow morphogen gradients, and investigate how such "spatial noise" changes at different stages within the gene regulatory network that controls wing vein patterning. Second, we will pursue recent evidence suggesting that patterning is sensitive not only to levels of morphogen in a gradient but to the local gradient slope as well. As part of this work we will test the hypothesis that slope detection is mediated by the Fat signaling pathway, and serves the purpose of reducing spatial noise. Third, we will extend previous mathematical models of morphogen gradient formation and interpretation in order to elucidate the tradeoffs that arise among regulatory mechanisms that serve as strategies for achieving robustness with respect to individual types of perturbations. In particular, such models will incorporate mechanisms and performance objectives that have not heretofore been analyzed mathematically. Broadly, the goal of this work is to provide a more coherent understanding of how complex regulation of spatially dynamic biological systems is utilized to achieve robust performance under a wide variety of conditions. Ultimately, the results should provide insights into the pathological processes that lead to structural birth defects and other developmental abnormalities. ) PUBLIC HEALTH RELEVANCE: Were it not for the remarkable accuracy and reliability of embryonic and fetal development, birth defects would be far more common than they are. To understand how reliability is achieved, we are focusing on the process of pattern formation in the fruit fly wing, about which there is a great deal of mechanistic knowledge. By showing how complex regulatory circuitry enables robust pattern formation, we will gain general insights into how development succeeds so often, why it occasionally fails, and how the causes of such failures might be identified.