Colonizing while migrating: how do individual enteric neural crest cells behave?

Abstract

BackgroundDirected cell migration is essential for normal development. In most of the migratory cell populations that have been analyzed in detail to date, all of the cells migrate as a collective from one location to another. However, there are also migratory cell populations that must populate the areas through which they migrate, and thus some cells get left behind while others advance. Very little is known about how individual cells behave to achieve concomitant directional migration and population of the migratory route. We examined the behavior of enteric neural crest-derived cells (ENCCs), which must both advance caudally to reach the anal end and populate each gut region.ResultsThe behavior of individual ENCCs was examined using live imaging and mice in which ENCCs express a photoconvertible protein. We show that individual ENCCs exhibit very variable directionalities and speed; as the migratory wavefront of ENCCs advances caudally, each gut region is populated primarily by some ENCCs migrating non-directionally. After populating each region, ENCCs remain migratory for at least 24 hours. Endothelin receptor type B (EDNRB) signaling is known to be essential for the normal advance of the ENCC population. We now show that perturbation of EDNRB principally affects individual ENCC speed rather than directionality. The trajectories of solitary ENCCs, which occur transiently at the wavefront, were consistent with an unbiased random walk and so cell-cell contact is essential for directional migration. ENCCs migrate in close association with neurites. We showed that although ENCCs often use neurites as substrates, ENCCs lead the way, neurites are not required for chain formation and neurite growth is more directional than the migration of ENCCs as a whole.ConclusionsEach gut region is initially populated by sub-populations of ENCCs migrating non-directionally, rather than stopping. This might provide a mechanism for ensuring a uniform density of ENCCs along the growing gut.

Building a second brain in the bowel

“…Consistent with this latter hypothesis, MMP2 inhibition slows ENCDC migration (66). Preferential ENCDC migration along neurites (48,67) might also help cells navigate gut mesenchyme to preexisting gaps in the ECM. These hypotheses might explain why chain migration is more efficient than migration by isolated ENCDCs.…”

“…One hypothesis is that cells at the front of the migrating ENCDC chain pull trailing ENCDCs via L1CAM-mediated adhesion. This seems unlikely, as migrating ENCDCs constantly change position, moving over each other (47,48). Another possibility is that ENCDCs enhance bowel colonization by altering ECM to enhance migration (65) or by degrading ECM to create spaces through which to migrate.…”

“…The absence of essential intrinsic guidance cues for rostrocaudal migration is likely, as ENCDCs migrate in either direction through aganglionic bowel (47)(48)(49) and bypass a cecal zone with high concentrations of the chemoattractant GDNF (47). Theoretical modeling suggests that rostrocaudal bowel colonization is driven by ENCDC proliferation, which causes competition for space and trophic factor (ref.…”

Neural crest migration is driven by a few trailblazer cells with a unique molecular signature narrowly confined to the invasive front

“…NC cells emerge from the dorsal neural tube and are sculpted by intrinsic and extrinsic signals into discrete, multicellular streams throughout the head and trunk (Kulesa and Gammill, 2010). Analysis of cell behaviors from in vivo time-lapse imaging in chick Fraser, 1998, 2000;Teddy and Kulesa, 2004;Kulesa et al, 2008;McKinney and Kulesa, 2011;Ridenour et al, 2014) and in chick and mouse intestine (Young et al, 2004(Young et al, , 2014Nishiyama et al, 2012) has shown that there are regional differences in cell speed, direction, proliferation, calcium activity and cell morphology depending on cell position within an NC migratory stream. We previously showed that a computational model of NC cell migration, using the chick cranial NC cell behavioral data, predicted that successful cell persistence of direction and stream cohesion would result from the presence of unique lead and trailing subpopulations (McLennan et al, 2012).…”

Emerging roles of gut microbiota and the immune system in the development of the enteric nervous system

“…Unlike enteric neurons, which are located exclusively within enteric ganglia, enteric glial cells (EGCs) are also found within interganglionic tracts, the smooth muscle layers, and the lamina propria of the mucosa (7)(8)(9). Both lineages of the ENS are derived from neuroectodermal progenitors, which delaminate from the neural crest and colonize the gut during embryogenesis (10)(11)(12)(13)(14). Enteric neurogenesis commences as soon as neural crest cells invade the gut (in the mouse at around embryonic day 9.0-9.5), peaks at mid-gestation, and continues, albeit at a decreasing pace, for the remaining fetal period and early postnatal life, until it terminates after weaning (15)(16)(17).…”