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Gastroenterology. 2019 Jan 2. pii: S0016-5085(18)35435-0. doi: 10.1053/j.gastro.2018.12.020. [Epub ahead of print]

Neuronal Development and Onset of Electrical Activity in the Human Enteric Nervous System.

Author information

1
Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N, UK.
2
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
3
Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N, UK; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
4
Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N, UK; Department of Gastroenterology, Great Ormond Street Hospital, London, UK. Electronic address: n.thapar@ucl.ac.uk.

Abstract

BACKGROUND & AIMS:

The enteric nervous system (ENS) is the largest branch of the peripheral nervous system, comprising complex networks of neurons and glia, which are present throughout the gastrointestinal (GI) tract. Although development of a fully functional ENS is required for GI motility, little is known about the ontogeny of ENS function in humans. We studied the development of neuronal subtypes and the emergence of evoked electrical activity within the developing human ENS.

METHODS:

Human fetal gut samples (obtained via the MRC-Wellcome Trust Human Developmental Biology Resource-UK) were characterized by immunohistochemistry, calcium imaging, RNAseq, and quantitative real-time PCR analyses.

RESULTS:

Human fetal colon samples have dense neuronal networks at the level of the myenteric plexus by embryonic week (EW) 12, with expression of excitatory neurotransmitter and synaptic markers. By contrast, markers of inhibitory neurotransmitters were not observed until EW14. Electrical train stimulation of internodal strands did not evoke activity within the ENS of EW12 or EW14 tissues. However, compound calcium activation was observed at EW16, which was blocked by the addition of 1μM tetrodotoxin. Expression analyses showed this activity was coincident with increases in expression of genes encoding proteins involved in neurotransmission and action potential generation.

CONCLUSIONS:

In analyses of human fetal intestinal samples, we followed development of neuronal diversity, electrical excitability, and network formation in the ENS. These processes are required to establish the functional enteric circuitry. Further studies could increase our understanding of the pathogenesis of a range of congenital enteric neuropathies.

KEYWORDS:

embryology; fetus; foetal; intestine

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