Vassilis Pachnis

Development and Homeostasis of the Nervous System Laboratory

We study how the nervous system develops and how its organisation and function are maintained in adult animals.

The central nervous system (CNS) and the ganglia of the peripheral nervous system (PNS) include many types of neurons and glia which have unique roles in the assembly and activity of neural circuits.

The aim of our research is to understand how the different types of nerve cells and glia are generated in the embryo and how they establish specific connections. We also study how the development and organisation of the nervous system is influenced by non-neural tissues and environmental factors.

Our goal is to discover genetic and molecular cascades implicated in the development, assembly and maintenance of two sets of neural circuits: those that are intrinsic to the gut wall and regulate gastrointestinal activity (enteric nervous system-ENS) and those that provide inhibition in the cerebral cortex.

Understanding how genes control neurogenesis and gliogenesis in these parts of the nervous system and identifying the cellular and molecular cascades that regulate their response to physiological and pathological changes is a major focus of our work. Progress in these areas will help us to address fundamental questions in developmental neuroscience and understand the pathogenesis of common congenital or acquired diseases associated with neural deficits.

The ENS of vertebrates

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. (Click to view larger image)

The ENS is an exceedingly complex neural network with many types of neurons and glial cells but no obvious topographic organisation. Neurons with different molecular profiles and physiological properties are scattered throughout the plexus of enteric ganglia and connect in an unpredictable manner. Despite their seemingly chaotic organisation, intestinal neural circuits control highly stereotypic activities of the gastrointestinal tract (such as peristalsis) and mediate reproducible responses of the gut wall to local and systemic signals.

We wish to determine how meaningful functional output (gut physiology) emerges from an apparently disordered neural network (ENS). How are different types of enteric neurons and glia generated from a pool of homogeneous progenitors and what is the logic that guides their connectivity? How stable are the molecular and physiological attributes of enteric neurons? How does the dynamic microenvironment of the gut influence the properties of individual enteric neurons and glia and the activity of the resident neuroglial networks?

Cognitive activity and complex behaviours depend on the assembly of functional neural circuits in the cerebral cortex. Cortical interneurons constitute a highly diverse population of locally projecting neurons which provide essential inhibition to the excitatory neurons of the cerebral cortex. Deficits of this neuronal subpopulation are associated with common neurodevelopmental and behavioural disorders.

Our goal is to identify and characterise the molecular genetic cascades that control the migration, fate restriction and differentiation of cortical interneuron progenitors. We also aim at understanding the molecular mechanisms that regulate the functional maturation of interneurons in concert with and in response to emerging neural activity.

Development of cortical interneurons

Development of cortical interneurons. Section through the forebrain of an embryonic day 18.5 mouse. The diffuse network of cortical interneurons (green cells) is seen in the cerebral cortex. Thalamocortical projections are shown in red. (Click to view larger image)

To address these questions we employ a wide spectrum of experimental approaches ranging from cell culture experiments to physiological and behavioural studies. We are using molecular, cellular and imaging approaches in conjunction with genetic manipulations to understand how multiple developmental signals converge to control gene expression and cell differentiation. An important component of our experimental toolkit is genetic in vivo fate mapping of individual progenitors which allows us to explore their developmental potential and test how it is modified by specific gene products.

Together our studies provide insight into the development and function of the nervous system under normal and pathological conditions.

Selected publications

Kabouridis PS, Lasrado R, McCallum S, Chng SH, Snippert HJ, Clevers H, Pettersson S, Pachnis V. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron. 2015 Jan 21;85(2):289-95. doi: 10.1016/j.neuron.2014.12.037. Epub 2015 Jan 8. PMID: 25578362 [PubMed - in process]

Sasselli, V; Boesmans, W; Berghe, PV; Tissir, F; Goffinet, A, M. and Pachnis, V (2013) Planar cell polarity genes control the connectivity of enteric neurons J Clin Invest. 2013 Apr;123(4):1763-72. doi: 10.1172/JCI66759. Epub 2013 Mar 8. PMID: 23478408 [PubMed - indexed for MEDLINE]

Denaxa, M; Kalaitzidou, M; Garefalaki, A; Achimastou, A; Lasrado, R; Maes, T and Pachnis, V (2012) Maturation-promoting activity of SATB1 in MGE-derived cortical interneurons Cell Reports 2, 1351-1362

Lopes, R; Verhey van Wijk, N; Neves, G and Pachnis, V (2012) Transcription factor LIM homeobox 7 (Lhx7) maintains subtype identity of cholinergic interneurons in the mammalian striatum Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3119-24. doi: 10.1073/pnas.1109251109. Epub 2012 Feb 6. PMID: 22315402

Laranjeira C, Sandgren K, Kessaris N, Richardson W, Potocnik A, Vanden Berghe P, Pachnis V. Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury. J Clin Invest. 2011 Sep;121(9):3412-24. doi: 10.1172/JCI58200. Epub 2011 Aug 25. PMID: 21865647 [PubMed - indexed for MEDLINE]

Vassilis Pachnis

vassilis.pachnis@crick.ac.uk
+44 (0)20 379 61556

  • Qualifications and history
  • 1980 MD University of Athens Medical School, Greece
  • 1986 PhD University of Pennsylvania, USA
  • 1986 Postdoctoral Fellow, Columbia University, USA
  • 1991 Group Leader, Medical Research Council National Institute for Medical Research, London, UK
  • 2015 Group Leader, the Francis Crick Institute, London, UK