Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players

Abstract

Hirschsprung disease (HSCR, intestinal aganglionosis) is a multigenic disorder with variable penetrance and severity that has a general population incidence of 1/5000 live births. Studies using animal models have contributed to our understanding of the developmental origins of HSCR and the genetic complexity of this disease. This review summarizes recent progress in understanding control of enteric nervous system (ENS) development through analyses in mouse models. An overview of signaling pathways that have long been known to control the migration, proliferation and differentiation of enteric neural progenitors into and along the developing gut is provided as a framework for the latest information on factors that influence enteric ganglia formation and maintenance. Newly identified genes and additional factors beyond discrete genes that contribute to ENS pathology including regulatory sequences, miRNAs and environmental factors are also introduced. Finally, because HSCR has become a paradigm for complex oligogenic diseases with non-Mendelian inheritance, the importance of gene interactions, modifier genes, and initial studies on genetic background effects are outlined.

Influence of Commensal Microbiota on the Enteric Nervous System and Its Role in Neurodegenerative Diseases

“…The defects are a result of incomplete migration of neural crest-derived stem cells along the gut axis. The underlying mechanism is multigenic and many different genes that promote the survival, proliferation, differentiation, and migration of enteric neural crest cells are involved [for a concise review, see 34]. …”

Development of the Enteric Nervous System: A Genetic Guide to the Perplexed

“…Congenital aganglionoses are, despite heterogeneity, referred to collectively as Hirschsprung disease [congenital megacolon], which is a multigenic disorder with variable penetrance that may involve short or long segments of bowel. 8–10 Whether an aganglionic region is long or short, acquired or congenital, survival requires that the aganglionic bowel be removed surgically. The results of the surgical excision of an aganglionic region of gut, although life saving, are often disappointing in that dysmotility, enterocolitis, and soiling may persist despite the complete removal of aganglionic tissue.…”

“…Examples of ENS hyperplasia are intestinal ganglioneuromatosis, which occurs in association with neurofibromatosis type 1 and multiple endocrine neoplasia 2B, 16–18 and intestinal neuronal dysplasia type B, which involves hyperplastic ganglia in the submucosa. 18,19 Diffuse ENS hypoplasia also oc Given that ENS development is very complicated and that its formation involves the coordinated action of many genes, 10 it seems reasonable to expect that defects will arise during development that are not sufficient to cause an aganglionosis but that, nevertheless, are sufficient to cause functional abnormalities of the ENS. These defects could involve the number of enteric neurons, the relative proportions of the various neuronal phenotypes, or their interconnections.…”

“…No similar patterned germinal zones have been recognized in the bowel. Although a variety of transcription and growth factors have been identified that critically affect enteric neuronal and glia development, 10,20 transcriptional signatures of the kind that allow the differential lineage of maturity of CNS neurons to be inferred do not exist for the ENS. What is badly needed is a reference manual that describes the expression profiles of the regulators of transcription and signaling in sublineages of developing enteric neurons at different stages of ontogeny.…”

Neural Crest Cells Contribute an Astrocyte-like Glial Population to the Spleen

“…Hirschsprung’s disease (HSCR, Online Mendelian Inheritance in Man #142623) results from defective NCC migration to, and colonization of, the hindgut during embryonic development14. Most commonly, HSCR results from mutations in Rearranged during transfection (Ret ) or Endothelin Receptor B (EdnrB ), both of which are required for NCC migration15.…”