A group of neurons, glial cells and immune cells within the gut wall.

Vassilis Pachnis : Areas of interest

Introduction

We study the enteric nervous system in order to understand how complex neural networks develop, how they interact with non-neural tissues and how they are affected by disease.

To understand how the daunting complexity and elaborate architecture of the nervous system emerge during development we study the neural networks of the gastrointestinal tract.

The human gut contains 100 million neurons and many more glial cells which form a continuous cellular mosaic extending throughout the organ. This so-called enteric nervous system (ENS) is in constant communication with the brain but can work independently from it to control vital functions of the gastrointestinal tract.

Image of the enteric nervous system in mice and fish.

Figure 1: The ENS of vertebrates. A, Neural crest-derived ENS progenitors (green) in the process of colonising the foregut of a mid-gestation mouse embryo. B, Enteric ganglia in the gut of adult mice include multiple types of enteric neurons. C, The neural network in the gut of a feeding zebrafish larva.

The myriads of neurons and glial cells of the ENS originate from a small and homogeneous group of cells, which leave the brain during embryogenesis, invade the gut wall and generate the local neural networks. How does this small group of ENS founder cells expand and diversify during development to generate the vast collection of enteric neurons and glia of the adult gut? How are the neurons and glial cells of the gut assembled into information processing networks? How does the chaotic networks of enteric neurons generate stereotypic and effective functional outputs?

To answer these questions we study the ENS of two model organisms, the mouse and zebrafish. At the core of our experimental strategy are state-of-the-art molecular, genetic, bioinformatics and imaging tools. We follow individual ENS progenitors and their descendants from early embryonic stages all the way to the adult in order to analyse their developmental potential. We study the transcriptional profile of single or pools of ENS cells at sequential developmental stages to understand how neuronal and glial cell diversity emerges. We ablate or modify the expression of specific genes and study the anatomical and functional consequences on the ENS and the gut. Fluorescent reporter expression in conjunction with high-resolution imaging allows us to study the spatial arrangement of enteric neurons and their projections in order to identify fundamental modules of ENS organisation. In our work we make extensive use of bioinformatics and computational tools.

Formation of the ENS is fully integrated into the developmental programmes of all the other tissues of the gut. Not surprisingly therefore, non-neural tissues, such as the immune system or the epithelial lining of the gut, influence the development of the ENS during embryogenesis and postnatal life. In addition, the ENS has profound effects on the formation and function of surrounding tissues. Our work tries to identify molecules and signals that mediate this two-way communication between neural and non-neural tissues of the gut.

The gut harbours vast and complex microbial communities that have profound effects on host physiology. We use molecular and genetic strategies to understand the nature and the mechanisms by which microbe-derived factors influence the development of the ENS.

Understanding the elaborate developmental programmes guiding the formation of intestinal neural circuits and the intricate tissue interactions that integrate their activity into gut physiology is an essential first step for elucidating the pathogenesis of common and often severe gastrointestinal disorders. Cellular and molecular knowledge emerging from our studies can open new avenues for the development of effective therapeutic strategies.

Selected publications