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Developmental Biology - Regenerative Medicine

Direction of Nerve Fibers Dictates Head to Toe Axis

Flatworm computer model explains and helps control whole body regeneration...

Biologists at Tufts University have developed a computational model of the flatworm — planaria — as it regenerates. This model explains how even fragments of a planaria can determine which end of which fragment will form a tail and which fragment end will form a head. This begins to answer an important question in regeneration research - which signals determine which anatomical structures?

Combining their models with experiments, researchers found nerve fiber direction determines which chemical signals establish an animals' head-to-tail axis. The model correctly predicted outcomes of genetic, pharmacological, and surgical manipulation in planaria — even which worm bits will construct two heads or two tails.

Using a new open-source platform called Planarian Interface for Modeling Body Organization or (PLIMBO), the computed model incorporates biological mechanisms that drive regeneration - some previously published, others just identified by this study. At cellular, tissue, and whole organism levels, it has helped identify regeneration neurons by molecular guided growth and organization of cells into tissues and anatomical structures. The researchers found that neurons played a critical role in reconstructing the polarity of the body plan (head to tail).

The model is basically a 2-dimensional map of a planarian body. Important signaling molecules such as Hh, NRF, ERK, Wnt, cAMP, beta-Cat, Ptc and APC, each followed their own rules of production, distribution and movement along cell paths, to interact with each other. To better understand the regeneration process, the authors cut out portions of each 'planarian map', inhibiting transport of its virtual morphogens, and/or perturbing the production of specific morphogens. Results of these cuts were then examined experimentally by exposing them to RNAi or pharmacological treatments, which can decrease or increase production of specific morphogens.

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

While it has been known for decades that neurons are important for regeneration, this is the first study to reveal how. Neuron directionality specifically instructs distribution of biochemicals which determine anatomic polarity of body axis. This shows how ordered pattern arises at the single cell level and is propagated to tissues and organs.

"The model did remarkably well in predicting the actual biological outcomes in the worm," said Michael Levin, Ph.D., Vannevar Bush Professor of Biology in the School of Arts & Sciences and director of the Allen Discovery Center at Tufts. "It enabled us to visualize how patterning information can percolate up from the cell- to the organism-level, and how directionality of specific cells (such as neurons) drive downstream biochemical gradients and organ determination. The model enabled us to make accurate predictions of new experiments that had never been done before, revealing that neural directionality trumps (and re-sets) pre-existing biochemical gradients."

Neural direction guides polarity in regeneration by serving as a rapid conduit for certain morphogens. Neurons contain within them a system of "tracks" called microtubules, and molecular "engines" that transport molecules along those tracks. The engines include dynein and kinesin, and inhibiting either of those molecules can lead to regeneration anomalies predicted by the model. Novel experiments showed, as predicted by the model, that pre-existing gradients of chemicals in fragments did not set the direction of the head and tail axis, but rather were re-written by the directionality of neuron fibers.

"PLIMBO permits us to examine regeneration in a quantitatively rigorous manner. We can fill in gaps in knowledge by simulating the role of neurons and novel morphogens and seeing if they improve the ability to predict experimental outcomes. This can provide us with not only a better understanding into the process of regeneration, tissue and organ formation but also insights into how body patterns could be disrupted in other animals during gestation, leading to birth defects."

Alexis Pietak PhD, biophysicist who devised the model at the Allen Discovery Center, and lead author.

Abstract
Control of axial polarity during regeneration is a crucial open question. We developed a quantitative model of regenerating planaria, which elucidates self-assembly mechanisms of morphogen gradients required for robust body-plan control. The computational model has been developed to predict the fraction of heteromorphoses expected in a population of regenerating planaria fragments subjected to different treatments, and for fragments originating from different regions along the anterior-posterior and medio-lateral axis. This allows for a direct comparison between computational and experimental regeneration outcomes. Vector transport of morphogens was identified as a fundamental requirement to account for virtually scale-free self-assembly of the morphogen gradients observed in planarian homeostasis and regeneration. The model correctly describes altered body-plans following many known experimental manipulations, and accurately predicts outcomes of novel cutting scenarios, which we tested. We show that the vector transport field coincides with the alignment of nerve axons distributed throughout the planarian tissue, and demonstrate that the head-tail axis is controlled by the net polarity of neurons in a regenerating fragment. This model provides a comprehensive framework for mechanistically understanding fundamental aspects of body-plan regulation, and sheds new light on the role of the nervous system in directing growth and form.

Author summary
Understanding how large-scale anatomy emerges from the activity of cellular pathways is a key goal of evolutionary developmental biology. Elucidating the rules of body-wide morphogenesis is especially essential for transitioning molecular signaling data at the cellular level into advances in regenerative biomedicine. We constructed and analyzed a comprehensive, multiscale computational model to explain the determination of axial polarity during planarian regeneration. Uniquely, our model explains the various head-tail patterning outcomes of a wide range of molecular and physiological manipulations. Testing the novel predictions of this model revealed the nervous system as an instructive regulator of axial patterning.

Authors
Pietak A, Johanna Bischof, post-doctoral scholar, Joshua LaPalme, research technician, and Junji Morokuma, research associate.

The authors have declared that no competing interests exist.

Acknowledgements
Funding: This work was supported by an Allen Discovery Center award from The Paul G. Allen Frontiers Group (12171). The authors gratefully acknowledge support from the National Institutes of Health (AR055993, AR061988), the G. Harold and Leila Y. Mathers Charitable Foundation (TFU141), National Science Foundation award # CBET-0939511, the W. M. KECK Foundation (5903), and the Templeton World Charity Foundation (TWCF0089/AB55). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

This work was supported by an Allen Discovery Center award from The Paul G. Allen Frontiers Group (12171), the National Institutes of Health (AR055993, AR061988, S10 OD021634), the G. Harold and Leila Y. Mathers Charitable Foundation (TFU141), National Science Foundation award #CBET-0939511, the W. M. KECK Foundation (5903), and the Templeton World Charity Foundation (TWCF0089/AB55). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

About Tufts University
Tufts University, located on campuses in Boston, Medford/Somerville and Grafton, Massachusetts, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.

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Apr 26 2019 Fetal Timeline Maternal Timeline News

A conceptual summary of anterior-posterior axis control in planaria regeneration.
CREDIT: Mohammed AlQuraishi, Harvard Medical School.