Gut regulates brain synaptic assembly through neuroendocrine signaling pathway

Background

The nervous system is the most complex tissue generated during development. Many types of neurons have to be created and connected in specific ways to form the circuits that support behavior. Connections between neurons are called ‘synapses.’ The fully developed nervous system contains  a huge number of these connections; the adult human brain contains in excess of 100 trillion synapses. How these connections are specified during development is poorly understood and remains a critical question in neurobiology. The roundworm C. elegans is a powerful model to study the genetic pathways that mediate the formation of synapses. Although much simpler than the human brain, the worm brain contains thousands of synapses that must be generated during development.  Many studies have demonstrated that the simple worm brain uses conserved molecular mechanisms to specify synapses. One critical and conserved signaling pathway that has emerged from studies of synapse formation in worms, flies, and mammals is the Wnt pathway. Wnt signaling mediates a myriad of developmental processes and has several well understood roles in synapse assembly. In their manuscript, Shi et al. report an unexpected mechanism by which Wnt signaling acts during C. elegans development to promote synapse formation: Wnt signaling in the gut regulates expression of a neuropeptide that potently affects synapse formation in the brain. These results are an exciting example of Wnt signaling regulating neuronal development via a mechanism that has not been previously reported.

 

Key Findings

By monitoring fluorescently tagged RAB-3, a component of synaptic vesicles, and SYD-1, a marker of synaptic active zones, Shi and colleagues were able to monitor synapse formation in vivo in a specific set of neurons, the AIY interneurons. With this fluorescent reporter system, the authors showed that the Wnt receptor CFZ-2 and its signaling partners SYS-1 (a beta-catenin-like factor) and POP-1 (a TCF homolog) promote the formation of AIY synapses but, remarkably, function in the intestine. How can signaling in the gut promote synapse assembly in the brain? The authors found that mutation of the prohormone proprotein convertase EGL-3, which is required for neuropeptide biogenesis, attenuates AIY presynaptic assembly, suggesting that neuropeptides are signals that promote AIY presynapse assembly. A screen of gut-produced neuropeptides reveals that silencing the expression of NLP-40 decreased AIY synapse formation. Furthermore, disruption of the Wnt pathway impaired expression of NLP-40 peptides in the gut. The authors next asked whether gut-derived neuropeptides might regulate synapse assembly by regulating neural activity. They observed reduced calcium signaling in AIY neurons of mutants lacking NLP-40, CFZ-2, or AEX-2, a receptor for the NLP-40 peptide (Doshi et. al 2019, Wang et al. 2013). Finally, the authors found evidence that the effects of gut-derived NLP-40 on synapse formation are not restricted to the AIY neurons. Loss of NLP-40 or loss of Wnt signaling reduced synapse formation in the entire nerve ring, indicating that gut-derived neuropeptides influence development of many synapses in the C. elegans brain.

 

Implications

These findings reveal an unexpected connection between the gut and brain development and a new mechanism by which Wnt signaling regulates neurodevelopment. In addition to reporting a new downstream target of Wnt signaling, this study might indicate roles for nutrients, the gut microenvironment, and the endocrine system in the development of brain circuits. These processes might play conserved roles in neurodevelopment and might suggest novel therapies for neurodevelopmental and neurodegenerative disorders. 

 

What we like about this preprint

This preprint presents a new mechanism by which the Wnt pathway regulates neurodevelopment through neuropeptide secretion in C. elegans. The authors performed a battery of experiments with thoughtful controls, monitoring fluorescence of two synaptic components to measure synapse formation. This study fills a critical gap in our understanding of C. elegans neuronal development and provides a framework for further investigation into the gut-brain axis during C. elegans neurodevelopment. 

 

Remaining questions

1.     What regulates the production of the Wnt ligand, especially in the gut?
2.     Can NLP-40 play a role in regulating post-synaptic neurons?
3.     Does NLP-40 act alone or in concert with other neuropeptides?
4.     How many synapses are affected by the Wnt-NLP-40 axis? Effects on development of synapses in the nerve ring suggest that many synapses might be regulated by this axis.
5.     When is Wnt signaling active during the worm development and how do dynamics of Wnt activity affect the NLP-40/AEX-2 axis during development?
6.     Can similar mechanisms affect synapse formation/remodeling post-developmentally? This would be a remarkable way to regulate behavior in response to metabolic or physiological cues.
7.     Why would the embryonic gut influence synapse formation? The worm embryo is ‘fed’ by yolk provided by the egg – perhaps this is a way that maternal metabolism can impact the brain development of the offspring.

References

Dockray, G.J. (2013). Enteroendocrine cell signalling via the vagus nerve. Curr Opin Pharmacol 13, 954-958.

Doshi, S., Price, E., Landis, J., Barot, U., Sabatella, M., Lans, H., and Kalb, R.G. (2019). Neuropeptide signaling regulates the susceptibility of developing C. elegans to anoxia. Free Radic Biol Med 131, 197–208

Wang, H., Girskis, K., Janssen, T., Chan, J.P., Dasgupta, K., Knowles, J.A., Schoofs, L., and Sieburth, D. (2013). Neuropeptide secreted from a pacemaker activates neurons to control a rhythmic behavior. Curr Biol 23, 746-754.

 

 

doi: https://doi.org/10.1242/prelights.27678

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