Self-Organizing Neural Networks in Novel Moving Bodies: Anatomical, Behavioral, and Transcriptional Characterization of a Living Construct with a Nervous System
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Abstract
A great deal is known about the formation and architecture of biological neural networks in animal models, which have arrived at their current structure-function relationship through evolution by natural selection. Little is known about the development of such structure-function relationships in a scenario where neurons are allowed to grow within evolutionarily-novel, motile bodies. Previous work showed that when a piece of ectodermal tissue is excised from Xenopus embryos and allowed to develop ex vivo , it will develop into a three-dimensional (3D) mucociliary organoid, and exhibits behaviors different from those observed in tadpoles of the same age. These ‘biological robots’ or ‘biobots’ are autonomous, self-powered, and able to move through aqueous environments. Here we report a novel type of biobot that is composed of ciliated epidermis and additionally incorporates neural tissue (neurobots). We show that neural precursor cells implanted within the Xenopus skin constructs develop into mature neurons and extend processes towards the outer surface of the bot as well as among each other. These self-organized neurobots show distinct external morphology, generate more complex patterns of spontaneous movements, and are differentially affected by neuroactive drugs compared to their non-neuronal counterparts. Calcium imaging experiments show that neurons within neurobots are indeed active. Transcriptomics analysis of the neurobots reveals increased variability of transcript profiles, expression of a plethora of genes relating to nervous system development and function, a shift toward more ancient genes, and up-regulation of neuronal genes implicated in visual perception.
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The increased complexity ofbiobotscould be a result of increased variability in the beating frequency of cilia in MCCs
If I'm understanding correctly, this might be a typo, should be neurobots.
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We speculate that this region is not truly empty and may be filled with extracellular matrix-like structures (ECM).
This is intriguing, would be nice to stain for fibronecting or collagen to see if ECM proteins are actually there. Or WFA labeling.
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nterestingly, we found that more than 54% of upregulated genesin neurobots fall into the two categories of most ancient genes (“All living organisms” and “Eukaryota”, Fig. 13a).
The comparison to sham NBs helps here, but there are also existing Xenopus developmental transcriptome data (e.g., early neural induction stages vs. later stages) that could provide context for whether activating these genes is a general feature of neural differentiation? Discussing this could help clarify and strengthen this claim. Additionally, some kind of ontology analysis of these genes would be interesting.
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In addition to Cluster 1, Cluster 12 (Supp. Fig. 7c) also included genes related to eye, lens,and retina development, including genes found in major retinal cell types42,i.e. retinal ganglion cells was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (whichthis version posted April 19, 2025. ; https://doi.org/10.1101/2025.04.14.648732doi: bioRxiv preprint
I found the upregulation of retinal genes in the neurobots without specific induction to be particularly interesting It makes me wonder if this hints at the activation of highly conserved, intrinsic transcriptional programs for light sensing that are relatively accessible or perhaps even a default pathway for neural precursors to explore during self-organization in such …
In addition to Cluster 1, Cluster 12 (Supp. Fig. 7c) also included genes related to eye, lens,and retina development, including genes found in major retinal cell types42,i.e. retinal ganglion cells was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (whichthis version posted April 19, 2025. ; https://doi.org/10.1101/2025.04.14.648732doi: bioRxiv preprint
I found the upregulation of retinal genes in the neurobots without specific induction to be particularly interesting It makes me wonder if this hints at the activation of highly conserved, intrinsic transcriptional programs for light sensing that are relatively accessible or perhaps even a default pathway for neural precursors to explore during self-organization in such novel contexts? Seems reminiscent of observations in brain organoids, which have also demonstrated an intrinsic ability to self-organize primitive sensory structures, sometimes even with spatial constraints. Though these neurobots are different than typical organoids, the fact that both systems originate neural precursors might suggests these cells might retain a latent capacity to access fundamental sensory development routines when placed in a permissive environment.
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