Balancing on the crest - Evidence for disruption of the enteric ganglia via inappropriate lineage segregation and consequences for gastrointestinal function

Abstract

Normal enteric nervous system (ENS) development relies on numerous factors, including appropriate migration, proliferation, differentiation, and maturation of neural crest (NC) derivatives. Incomplete rostral to caudal migration of enteric neural crest-derived progenitors (ENPs) down the gut is at least partially responsible for the absence of enteric ganglia that is a hallmark feature of Hirschsprung disease (HSCR). The thought that ganglia proximal to aganglionosis are normal has guided surgical procedures for HSCR patients. However, chronic gastrointestinal dysfunction suffered by a subset of patients after surgery as well as studies in HSCR mouse models suggest that aberrant NC segregation and differentiation may be occurring in ganglionated regions of the intestine. Studies in mouse models that possess enteric ganglia throughout the length of the intestine (non-HSCR) have also found that certain genetic alterations affect neural crest lineage balance and interestingly many of these mutants also have functional gastrointestinal (GI) defects. It is possible that many GI disorders can be explained in part by imbalances in NC-derived lineages. Here we review studies evaluating ENS defects in HSCR and non-HSCR mouse models, concluding with clinical implications while highlighting areas requiring further study.

Keywords: Enteric nervous system; Gastrointestinal function; Hirschsprung disease; Lineage segregation; Mouse models; Neural crest development.

Figure 1

Schematic diagram illustrating potential mechanisms by which alterations in gene expression or function could lead to multiple ENS defects. At left a typical normal myenteric ganglia is shown consisting of multiple neuronal subtypes (ChAT+ green, 5-HT+ dark blue, and GABA+ peach). Enteric glia normally reside within the ganglia, along inter-ganglia fibers, and within the underlying muscle (grey ovals/stellate cell shapes). Changes in neuron and glia numbers and imbalance of specific neuronal subtypes (such as the decrease in CHAT+ neurons seen in the inset, fewer green neuronal cell bodies) have already been described in some mouse mutants. These alterations — as well as more subtle changes — could disrupt the electrical properties of neurons and glia thus interfering with signaling between ENS components and other cell types like those of the immune system. Such changes could ultimately result in GI dysfunction due to deficits in motility and inappropriate immune response.