Insights into the development of our second brain

18th May 2017

Glial cells (red) of the enteric nervous system in the villi, the projections of the gut lining

Glial cells (red) of the enteric nervous system in the villi, the projections of the gut lining. Image by Aimee Parker.

A computational modeller at the Quadram Institute has helped unravel how the organization of the enteric nervous system develops. The study, led by the Francis Crick Institute, provides the first overview of how this essential part of the nervous system emerges in the embryo.

Neural development in the brain and spinal cord is relatively well understood. Cells develop, divide, specialise and interconnect according to defined rules, which we have a clear understanding of.  In contrast, we haven’t until now understood the principles behind the organization of the enteric nervous system.

A new study, published in the journal Science, describes the rules behind the emergence of the organisation of the enteric nervous system, the complex network of millions of interconnected neurons and glial cells that control the digestive system. Sometimes called the second brain, the enteric nervous system (ENS) regulates digestion, gut blood flow and motility. Although connected to the central nervous system, it is essentially an autonomous system. As we have become more aware of its crucial role in maintaining a healthy gut and its links to digestive diseases, understanding how it develops and organises itself has become more important.

ENS cells derive from a small cluster of cells in the embryo called the neural crest. Some of these cells colonize the embryonic gut and, through proliferation, migration and differentiation, give rise to several types of neurons and associated glial cells organized in interconnected ganglia throughout the gut wall. Cell division, migration and differentiation as well as connectivity is guided by developmental “rules” that integrate spatial cues and other signalling pathways. These rules ensure that the required cell types are in the right location and interconnect with each other and other gut elements, such as smooth muscle layers and immune and epithelial cells, to orchestrate the functionality of the gut.

Glial cells (pink) at the bottom of a crypt in the gut lining. Image by Aimee Parker

Glial cells (pink) at the bottom of a crypt in the gut lining. Image by Aimee Parker

To work out the principles that guide ENS development, the researchers integrated experimental and mathematical modelling techniques. Using a genetic cell labelling experimental strategy, they could trace the descendants of single cells originally labelled in the embryo and get a picture of their spatial distribution in the adult gut. This provided a very valuable insight into cell behaviour and required the use of mathematical models to understand in depth the rules and principles guiding the spatiotemporal distribution of the label during development.

Dr Carmen Pin from the Quadram Institute, based on these observations, built computational and analytical models which revealed the spatiotemporal patterns followed by ENS cells during development.

“We have demonstrated the importance of multidisciplinary studies to address relevant unanswered questions in biology that can have an immediate impact on people’s health and wellbeing” said Dr Carmen Pin

Modelling results and experimental evidence together suggested that the enteric nervous system is organized in overlapping clonal cell units whose size and shape are determined by the proliferation potential of the founder cell, local spatial interactions of its descendants with lineally related and unrelated cells and the growth of the gut during development.  These clonal units extend in the axial direction of the gut to form columns that run across all the gut wall layers. The researchers also showed that the cell lineages linked to overall function, as sister cells responded to stimulation in a synchronised way.

As well as giving insights in the development of our ‘second brain’ it’s hoped that these findings might help in the diagnosis and treatment of diseases of the enteric nervous system.

Reference: Lineage-dependent Spatial and Functional Organization of the Mammalian Enteric Nervous System” Reena Lasrado, Werend Boesmans, Jens Kleinjung, Carmen Pin, Donald Bell, Leena Bhaw, Sarah McCallum, Hui Zong, Liqun Luo, Hans Clevers, Pieter Vanden Berghe, and Vassilis Pachnis. Science Vol. 356, Issue 6339, pp. 722-726 DOI: 10.1126/science.aam7511

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