Enteric Nervous System: Development and Developmental Disturbances—Part 1

This review, which is presented in two parts, summarizes and synthesizes current views on the genetic, molecular, and cell biological underpinnings of the early embryonic phases of enteric nervous system (ENS) formation and its defects. In the first part, we describe the critical features of two principal abnormalities of ENS development: Hirschsprung's disease (HSCR) and intestinal neuronal dysplasia type B (INDB) in humans, and the similar abnormalities in animals. These represent the extremes of the diagnostic spectrum: HSCR has agreed and unequivocal diagnostic criteria, whereas the diagnosis and even existence of INDB as a clinical entity is highly controversial. The difficulties in diagnosis and treatment of both these conditions are discussed. We then review the genes now known which, when mutated or deleted, may cause defects of ENS development. Many of these genetic abnormalities in animal models give a phenotype similar or identical to HSCR, and were discovered by studies of humans and of mouse mutants with similar defects. The most important of these genes are those coding for molecules in the GDNF intercellular signaling system, and those coding for molecules in the ET-3 signaling system. However, a range of other genes for different signaling systems and for transcription factors also disturb ENS formation when they are deleted or mutated. In addition, a large proportion of HSCR cases have not been ascribed to the currently known genes, suggesting that additional genes for ENS development await discovery.

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Enteric Nervous System: Development and Developmental Disturbances—Part 2

Pediatric and Developmental Pathology ◽

10.1007/s10024-002-0002-4 ◽

2002 ◽

Vol 5 (4) ◽

pp. 329-349 ◽

Cited By ~ 127

Author(s):

Donald Newgreen ◽

Heather M. Young

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

System Development ◽

Molecular Genetic ◽

Nervous System Development ◽

Developmental Disturbances ◽

Genetic Abnormalities ◽

A Cell ◽

Cells Of Cajal ◽

Enteric Nervous System Development

This review, which is presented in two parts, summarizes and synthesizes current views on the genetic, molecular, and cell biological underpinnings of the early embryonic phases of enteric nervous system (ENS) formation and its defects. Accurate descriptions of the phenotype of ENS dysplasias, and knowledge of genes which, when mutated, give rise to the disorders (see Part 1 in the previous issue of this journal), are not sufficient to give a real understanding of how these abnormalities arise. The often indirect link between genotype and phenotype must be sought in the early embryonic development of the ENS. Therefore, in this, the second part, we provide a description of the development of the ENS, concentrating mainly on the origin of the ENS precursor cells and on the cell migration by which they become distributed throughout the gastrointestinal tract. This section also includes experimental evidence on the controls of ENS formation derived from classic embryological, cell culture, and molecular genetic approaches. In addition, for reasons of completeness, we also briefly describe the origins of the interstitial cells of Cajal, a cell population closely related anatomically and functionally to the ENS. Finally, a brief sketch is presented of current notions on the developmental processes between the genes and the morphogenesis of the ENS, and of the means by which the known genetic abnormalities might result in the ENS phenotype observed in Hirschsprung's disease.

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