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The BMP ligand Pinhead together with Admp supports the robustness of embryonic patterning.

ABSTRACT: Vertebrate embryonic dorsoventral axis is robustly stable in the face of variations in bone morphogenetic protein (BMP) signaling. However, the molecular mechanism behind this robustness remains uncharacterized. In this study, we show that zebrafish Pinhead, together with Admp, plays an important compensatory role in ensuring the robustness of axial patterning through fine-tuning of BMP signaling. pinhead encodes a BMP-like ligand expressed in the ventrolateral margin of the early gastrula. Transcription of pinhead and admp is under opposing regulation, where pinhead depletion results in a compensatory increase in admp transcription and vice versa, leading to normal axis formation in pinhead or admp mutants. Expression of pinhead and admp is directly repressed by the BMP/Smad pathway. When BMP signals were inhibited or excessively activated, pinhead/admp expression changed accordingly, allowing for self-regulation. Thus, this study reveals a negative feedback loop between BMP signaling and pinhead/admp that effectively stabilizes embryonic patterning by buffering against fluctuations in BMP signaling.

SUBMITTER: Yan Y

PROVIDER: S-EPMC6989304 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The BMP ligand Pinhead together with Admp supports the robustness of embryonic patterning.

Yan Yifang Y Ning Guozhu G Li Linwei L Liu Jie J Yang Shuyan S Cao Yu Y Wang Qiang Q

Science advances 20191218 12

Vertebrate embryonic dorsoventral axis is robustly stable in the face of variations in bone morphogenetic protein (BMP) signaling. However, the molecular mechanism behind this robustness remains uncharacterized. In this study, we show that zebrafish Pinhead, together with Admp, plays an important compensatory role in ensuring the robustness of axial patterning through fine-tuning of BMP signaling. <i>pinhead</i> encodes a BMP-like ligand expressed in the ventrolateral margin of the early gastrul ...[more]

PMID: 32064309

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Project description:Complex periodic patterns can self-organize through dynamic interactions between diffusible activators and inhibitors. In the biological context, self-organized patterning is challenged by spatial heterogeneities ('noise') inherent to biological systems. How spatial variability impacts the periodic patterning mechanism and how it can be buffered to ensure precise patterning is not well understood. We examine the effect of spatial heterogeneity on the periodic patterning of the fruit fly eye, an organ composed of ?800 miniature eye units (ommatidia) whose periodic arrangement along a hexagonal lattice self-organizes during early stages of fly development. The patterning follows a two-step process, with an initial formation of evenly spaced clusters of ?10 cells followed by a subsequent refinement of each cluster into a single selected cell. Using a probabilistic approach, we calculate the rate of patterning errors resulting from spatial heterogeneities in cell size, position and biosynthetic capacity. Notably, error rates were largely independent of the desired cluster size but followed the distributions of signaling speeds. Pre-formation of large clusters therefore greatly increases the reproducibility of the overall periodic arrangement, suggesting that the two-stage patterning process functions to guard the pattern against errors caused by spatial heterogeneities. Our results emphasize the constraints imposed on self-organized patterning mechanisms by the need to buffer stochastic effects. Author summary Complex periodic patterns are common in nature and are observed in physical, chemical and biological systems. Understanding how these patterns are generated in a precise manner is a key challenge. Biological patterns are especially intriguing, as they are generated in a noisy environment; cell position and cell size, for example, are subject to stochastic variations, as are the strengths of the chemical signals mediating cell-to-cell communication. The need to generate a precise and robust pattern in this 'noisy' environment restricts the space of patterning mechanisms that can function in the biological setting. Mathematical modeling is useful in comparing the sensitivity of different mechanisms to such variations, thereby highlighting key aspects of their design.We use mathematical modeling to study the periodic patterning of the fruit fly eye. In this system, a highly ordered lattice of differentiated cells is generated in a two-dimensional cell epithelium. The pattern is first observed by the appearance of evenly spaced clusters of ?10 cells that express specific genes. Each cluster is subsequently refined into a single cell, which initiates the formation and differentiation of a miniature eye unit, the ommatidium. We formulate a mathematical model based on the known molecular properties of the patterning mechanism, and use a probabilistic approach to calculate the errors in cluster formation and refinement resulting from stochastic cell-to-cell variations ('noise') in different quantitative parameters. This enables us to define the parameters most influencing noise sensitivity. Notably, we find that this error is roughly independent of the desired cluster size, suggesting that large clusters are beneficial for ensuring the overall reproducibility of the periodic cluster arrangement. For the stage of cluster refinement, we find that rapid communication between cells is critical for reducing error. Our work provides new insights into the constraints imposed on mechanisms generating periodic patterning in a realistic, noisy environment, and in particular, discusses the different considerations in achieving optimal design of the patterning network.

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The BMP ligand Pinhead together with Admp supports the robustness of embryonic patterning.

Publications

The BMP ligand Pinhead together with Admp supports the robustness of embryonic patterning.

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