Development of the human gastrointestinal tract: Twenty years of progress

doi:10.1016/S0016-5085(99)70193-9

Gastroenterology

Volume 116, Issue 3, March 1999, Pages 702-731

https://doi.org/10.1016/S0016-5085(99)70193-9 Get rights and content

Abstract

A combination of approaches has begun to elucidate the mechanisms of gastrointestinal development. This review describes progress over the last 20 years in understanding human gastrointestinal development, including data from both human and experimental animal studies that address molecular mechanisms. Rapid progress is being made in the identification of genes regulating gastrointestinal development. Genes directing initial formation of the endoderm as well as organ-specific patterning are beginning to be identified. Signaling pathways regulating the overall right-left asymmetry of the gastrointestinal tract and epithelial-mesenchymal interactions are being clarified. In searching for extrinsic developmental regulators, numerous candidate trophic factors have been proposed, but compelling evidence remains elusive. A critical gene that initiates pancreas development has been identified, as well as a number of genes regulating liver, stomach, and intestinal development. Mutations in genes affecting neural crest cell migration have been shown to give rise to Hirschsprung's disease. Considerable progress has been achieved in understanding specific phenomena, such as the transcription factors regulating expression of sucrase-isomaltase and fatty acid–binding protein. The challenge for the future is to integrate these data into a more complete understanding of the physiology of gastrointestinal development.

GASTROENTEROLOGY 1999;116:702-731

Section snippets

Effects of fetal environment on gastrointestinal tract development

Cells of the fetal gastrointestinal tract are exposed to potential extrinsic growth regulators from three sources: (1) the circulation, carrying factors that cross the placenta from the maternal blood, factors produced by the placenta itself, and factors secreted by fetal tissue; (2) the amniotic fluid, carrying factors produced by the extraembryonic membranes or secreted by the fetus; and (3) paracrine and autocrine factors produced by the fetal tissues, which act locally. After birth,

Morphogenesis and differentiation

The esophagus can be identified as a distinct structure early in embryogenesis (4 weeks); it elongates during subsequent development relatively more rapidly than the fetus as a whole.⁴ At 10 weeks, ciliated columnar epithelium appears in the esophagus. Stratified squamous epithelium replaces it at around 20–25 weeks, a process that begins in the midesophagus and proceeds both caudad and cephalad.⁶⁸ This process has not been studied further, but development of human fetal esophageal mucosa has

Morphogenesis

The morphological and histological development of the stomach is complete at term.⁴ Prenatal ultrasound examinations have shown that the fetal stomach grows in a linear fashion from 13 to 39 weeks and that the characteristic anatomic features (greater curvature, lesser curvature, fundus, body, and pylorus) can be identified by 14 weeks. Abnormal images can identify the presence of congenital anomalies. Failure to delineate the fetal stomach ultrasonographically in the second trimester indicates

Morphogenesis

Morphogenesis of the human pancreas has been described in detail previously⁴ and will be recapitulated only briefly. Formation of the pancreas is initiated by the emergence of dorsal and ventral pancreatic buds on opposite sides of the foregut. As these epithelial buds enlarge, a treelike ductal system develops by growth and branching. As the gut tube grows and rotates, the two pancreatic buds come together and fuse at about the seventh week of gestation. Individual endocrine cells are

Morphogenesis and differentiation

The ontogeny of the small intestine can be thought of as proceeding through three successive phases: morphogenesis and cell proliferation, cell differentiation, and cellular and functional maturation.¹²⁸ By 13 weeks of gestation, organogenesis of the intestine is complete.¹²⁹ Organ morphogenesis is well described in standard texts and will not be considered in detail. The major milestones are indicated in Table 1. New data on the process and regulation of cellular differentiation that have

Morphogenesis and differentiation

A striking characteristic of the developing fetal colon is its initial similarity to the small intestine. The development of the colon is marked by three important cytodifferentiative stages: the appearance (from about 8 to 10 weeks) of a primitive stratified epithelium, similar to that found in the early development of the small intestine; the conversion of this epithelium to a villus architecture with developing crypts (about 12–14 weeks); and the remodeling of the epithelium at around 30

Conclusions

Important progress has been made in understanding the development of the human gastrointestinal tract over the last two decades. Techniques of molecular biology have facilitated the analysis of complex mechanisms of developmental regulation, providing model systems capable of elucidating human disorders. Synthesis of data from diverse approaches will be required to define the integrated physiology of the developing gastrointestinal tract and the alterations leading to congenital anomalies.

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^☆: Address requests for reprints to: Robert K. Montgomery, Ph.D., Division of Pediatric Gastroenterology and Nutrition, The Floating Hospital for Children, 750 Washington Street, Box 383, Boston, Massachusetts 02111-1533. e-mail: [email protected]; fax: (617) 636-4233.

^☆☆: Supported in part by National Institutes of Health research grant DK 32658, Pediatric Gastroenterology Research Training grant DK 07471, and Digestive Disease Center grant P30 DK34928.

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Special Reports and ReviewsDevelopment of the human gastrointestinal tract: Twenty years of progress☆,☆☆

Abstract

Section snippets

Effects of fetal environment on gastrointestinal tract development

Morphogenesis and differentiation

Morphogenesis

Morphogenesis

Morphogenesis and differentiation

Morphogenesis and differentiation

Conclusions

Gastroenterology

Gastroenterology

Curr Top Dev Biol

Dev Biol

Dev Biol

J Biol Chem

Dev Biol

Cell

J Biol Chem

Gastroenterology

Cell

Exp Cell Res

Cell

Gastroenterology

Cell

Biochem Biophys Res Commun

Gastroenterology

Gastroenterology

Dev Biol

Cell

Gastroenterology

J Biol Chem

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterol Clin North Am

Gastroenterology

Gastroenterology

J Biol Chem

Gastroenterology

Gastroenterology

J Pediatr

J Pediatr

Biochim Biophys Acta

Gastroenterology

Gastroenterology

Gastroenterology

Clin Gastroenterol

Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps

N Engl J Med

Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population

Hum Mol Genet

Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease

Hum Mol Genet

Molecular genetics of early liver development

Annu Rev Physiol

Developmental biology of the pancreas

Development

Squid Pax-6 and eye development

Proc Natl Acad Sci USA

Mutations affecting development of zebrafish digestive organs

Development

Chimeric-transgenic mice represent a powerful tool for studying how the proliferation and differentiation programs of intestinal epithelial cell lineages are regulated

Proc Natl Acad Sci USA

Scatter factor/hepatocyte growth factor is essential for liver development

Nature

Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor

Nature

Special Reports and Reviews
Development of the human gastrointestinal tract: Twenty years of progress☆,☆☆