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Researchers unlock a new role for the nervous system in regeneration

Credit: CC0 Public Domain Biologists at Tufts University have developed a calculation model of planar (flatworm) regeneration that explains how fragments of planaria determine which end to form a tail and which should form a head. Development begins to respond to an important issue in regeneration research &#821 1; what signals determine the rebuilding of specific anatomical structures? By combining modeling and experimentation, the researchers determined that the direction of nerve fibers sets the redistribution of chemical signals that determine the direction of the head-to-tail axis. The model could also predict the results of many genetic, pharmacological and surgical manipulations, such as two-head worms or two tails. The result published in the journal PLOS Computational Biology goes beyond planaria and shows how computational modeling of physiological and genetic signals can help understand and control regeneration. The discovery that neural direction helps control the organ level structure can have many applications in biomedical contexts, such as regeneration in mammals, birth defects, bioengineering of organoids and cancer. The calculation model uses a new open source simulation platform called the Planarian Interface for Modeling Body Organization (PLIMBO), containing many biological mechanisms that drive regeneration, as previously published, and others discovered in the current study. This computing environment creates a realistic quantitative simulation of events that take place on molecular, cellular, tissue and whole organisms. The model helped identify the important role that neurons play in regeneration by providing active transport of morphogens – the molecules that help control the growth and organization of…

Credit: CC0 Public Domain

Biologists at Tufts University have developed a calculation model of planar (flatworm) regeneration that explains how fragments of planaria determine which end to form a tail and which should form a head. Development begins to respond to an important issue in regeneration research &#821

1; what signals determine the rebuilding of specific anatomical structures? By combining modeling and experimentation, the researchers determined that the direction of nerve fibers sets the redistribution of chemical signals that determine the direction of the head-to-tail axis. The model could also predict the results of many genetic, pharmacological and surgical manipulations, such as two-head worms or two tails.

The result published in the journal PLOS Computational Biology goes beyond planaria and shows how computational modeling of physiological and genetic signals can help understand and control regeneration. The discovery that neural direction helps control the organ level structure can have many applications in biomedical contexts, such as regeneration in mammals, birth defects, bioengineering of organoids and cancer.

The calculation model uses a new open source simulation platform called the Planarian Interface for Modeling Body Organization (PLIMBO), containing many biological mechanisms that drive regeneration, as previously published, and others discovered in the current study. This computing environment creates a realistic quantitative simulation of events that take place on molecular, cellular, tissue and whole organisms. The model helped identify the important role that neurons play in regeneration by providing active transport of morphogens – the molecules that help control the growth and organization of cells in different tissues and anatomical structures. The researchers found that neurons played an important role in reconstructing the polarity of the body plane (head to tail), and that morphogens can be rapidly distributed so that the regeneration process can function efficiently on different scales – from small fragments to complete organs.

Estimated redistribution of morphogens Erk, beta-cat and Notum after flatworm fragmentation. Reset gradients help determine the polarity of the fragment in regeneration. Credit: Alexis Pietak & Mike Levin, Tufts University

The model is basically a 2-dimensional map of a planic body, in which important signal molecules such as Hh, NRF, ERK, Wnt, cAMP, beta-cat, Ptc and APC follows its own rules for production, distribution and transport along cell lines and interacts with each other. To better understand the regeneration process, the authors examined the calculated results of cutting out portions of the map, inhibiting the transport of the virtual morphogens and / or interfering with the production of specific morphogens. The results of these procedures were then examined experimentally by physical excision in the mask and exposure to RNAi or pharmacological treatments, which may reduce or increase the biological production of specific morphogens. Although it has been known for decades that neurons are in any way important for regenerative capacity, this is the first study to reveal that it is neural direction that specifically describes subsequent redistribution of biochemical agents that determine the anatomical polarity of a larger body axis. This shows how ordered patterns occur on single cell scale and propagated into tissues and organs.

“The model did remarkably well in predicting the actual biological results of the snake,” said Michael Levin, Ph.D., Vannevar Bush Professor of Biology at School of Arts and Sciences and Director of the Allen Discovery Center at Tufts. “It allowed us to visualize how patterning information can percolate up from the cell to organism level and how the direction of specific cells (such as neurons) drives downstream biochemical gradients and organ determination. The model allowed us to make accurate predictions about new experiments as had never been done before and revealed that neural directional drums (and restores) existing biochemical gradients. “Neural direction controls the polarity of regeneration by acting as a quick guide to some morphogens. Neurons contain within them a system of “traces” called microtubules and molecular “motors” that transport molecules along these traces. The engines include dynein and kinesin, and inhibition of any of these molecules can lead to regeneration anomalies predicted by the model. New experiments showed, as predicted by the model, that the current existing gradients of chemicals in fragments did not set the direction of the head and tail axis, but rather were rewritten by the direction of neuronal fibers.

“PLIMBO permit us to investigate regeneration in a quantitatively rigorous manner,” said lead author Alexis Pietak, the biophysicist who designed the model and member of the Allen Discovery Center. “We can fill in gaps in knowledge by simulating the role of neurons and new morphogens. and see if they improve the ability to predict experimental results. This can give us not only a better understanding of the process of regeneration, tissue and organ formation, but also insights on how body patterns can interfere with other animals during pregnancy, leading to birth defects. “


Electric signals kick off regeneration of flatworm


More information:
Alexis Pietak et al., Neural control of the body plane axis in regenerating planaria, PLOS Computational Biology (2019). DOI: 10.1371 / journal.pcbi.1006904

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Researchers unlock new role for the nervous system in regeneration (2019, April 25)
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