Abstract
Vagal neural crest cells (VNCCs) arise in the hindbrain, and at (avian) embryonic day (E) 1.5 commence migration through paraxial tissues to reach the foregut as chains of cells 1–2 days later. They then colonise the rest of the gut in a rostrocaudal wave. The chains of migrating cells later resolve into the ganglia of the enteric nervous system. In organ culture, E4.5 VNCCs resident in the gut (termed enteric or ENCC) which have previously encountered vagal paraxial tissues, rapidly colonised aneural gut tissue in large numbers as chains of cells. Within the same timeframe, E1.5 VNCCs not previously exposed to paraxial tissues provided very few cells that entered the gut mesenchyme, and these never formed chains, despite their ability to migrate in paraxial tissue and in conventional cell culture. Exposing VNCCs in vitro to paraxial tissue normally encountered en route to the foregut conferred enteric migratory ability. VNCC after passage through paraxial tissue developed elements of retinoic acid signalling such as Retinoic Acid Binding Protein 1 expression. The paraxial tissue's ability to promote gut colonisation was reproduced by the addition of retinoic acid, or the synthetic retinoid Am80, to VNCCs (but not to trunk NCCs) in organ culture. The retinoic acid receptor antagonist CD 2665 strongly reduced enteric colonisation by E1.5 VNCC and E4.5 ENCCs, at a concentration suggesting RARα signalling. By FACS analysis, retinoic acid application to vagal neural tube and NCCs in vitro upregulated Ret; a Glial-derived-neurotrophic-factor receptor expressed by ENCCs which is necessary for normal enteric colonisation. This shows that early VNCC, although migratory, are incapable of migrating in appropriate chains in gut mesenchyme, but can be primed for this by retinoic acid. This is the first instance of the characteristic form of NCC migration, chain migration, being attributed to the application of a morphogen.
Highlights
The enteric nervous system (ENS) is produced largely from vagal level neural crest cells (VNCCs) arising adjacent to somites (s) 1–7 [1,2]
We propose that the change from ‘‘VNCC’’ to ‘‘ENCC’’ represents a real functional difference rather than terminological convenience, is accomplished at least in part by exposure to Retinoic acid (RA) normally derived from adjacent tissues, and is marked by increased expression of Ret and by the gain of ability to colonise the gut mesenchyme in large numbers as chains of cells
ENCCs form Chains in vivo at Initial Entry to the Foregut Sagittal slices of E2.5 quail embryos (HH16–18; N = 14) stained with antibodies to SoxE to label NCCs and E-Cadherin to label foregut endoderm displayed ENCC in spiralling chains usually 1–2 cells wide within the mesenchyme of the narrow foregut immediately caudal to the wide pharynx from the earliest stages of colonisation (Figure 1)
Summary
The enteric nervous system (ENS) is produced largely from vagal level neural crest cells (VNCCs) arising adjacent to somites (s) 1–7 [1,2]. VNCCs commence migrating from the avian neural tube at embryonic day (E) 1.5 (,10 somite stage), moving ventrally over and through the paraxial somites towards and into the foregut by E2.5–3 [3]. Once in the gut these cells are commonly referred to as enteric or ENCCs, and migrate as distinctive chains [6,7]. ENCCs subsequently differentiate and consolidate into aggregates to create the mature ENS [8]. This developmental process is broadly conserved in vertebrates [9]
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