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.

Gut feelings: Studying enteric nervous system development, function, and disease in the zebrafish model system

“…Specifically, it will cover the different steps of ENS development in Zebrafish, genes and signaling pathways that regulate ENS development, and how the Zebrafish model has aided work and understanding of the molecular basis of ENS diseases. For excellent reviews on other model organisms, see Goldstein and Nagy, ; Lake and Heuckeroth, ; Musser and Michelle Southard‐Smith, ; Obermayr et al, ; Bondurand and Southard‐Smith, ; Hao et al, ; Uesaka et al, .…”

Migration pathways of sacral neural crest during development of lower urogenital tract innervation

“…These migratory cells, termed neural crest-derived progenitor cells (NCPCs), express Sox10 and differentiate to form sensory and autonomic innervation for a variety of organs, including the lung, heart, kidney, and intestine (Freem et al, 2010; Itaranta et al, 2009; Lajiness et al, 2014; Lake and Heuckeroth, 2013; Musser and Southard-Smith, 2013; Obermayr et al, 2013; Verberne et al, 2000). Detailed spatiotemporal maps of neural crest derived innervation for these organs have been particularly informative for understanding disease processes.…”

Male‐specific colon motility dysfunction in the TashT mouse line

“…While the myenteric plexus notably controls intestinal motility in collaboration with the interstitial cells of Cajal (ICC)—the pacemaker cells of the bowel, the submucosal plexus regulates several mucosal functions . To perform these tasks, each plexus must contain appropriate density of ganglia and adequate proportions of neuron subtypes and glial cells within each ganglion …”

“…3 To perform these tasks, each plexus must contain appropriate density of ganglia and adequate proportions of neuron subtypes and glial cells within each ganglion. 4 Failure of neural crest-derived ENS progenitors to properly reach the distal bowel during prenatal development may cause Hirschsprung disease (HSCR), which affects one in 5000 live births with a 4 : 1 male to female ratio. [5][6][7] HSCR is a life-threatening condition characterized by functional obstruction in the distal bowel due to the lack of enteric neural ganglia (aganglionosis).…”