Embryology and Development
Gastrulation occurs 2 weeks after fertilization, inducing a massive rearrangement of the embryo. It transforms a relatively uniform cell ball into a multilayered organism with recognizable body plans. Some cells divide faster than others, resulting in a change in embryonic shape. Cells converge on the embryonic midline. As they crowd together, they push each other toward the future head and tail, and the embryo lengthens.
There are two major steps in gastrointestinal (GI) development: The formation of the gut tube and the formation of individual organs each with their own specialized cell types (1). These events are regulated by homeobox or Hox genes (2), particularly Cdx1 and Cdx2, which are only expressed in the intestine. These two genes are important in the anterior to posterior patterning of the intestines and in defining patterns of proliferation and differentiation along the crypt–villus axis (3). Their importance in intestinal differentiation is important not only in normal intestinal development, but also in the development of intestinal metaplasia in the stomach and in Barrett esophagus as discussed in Chapters 2, 3, 4. Other signaling cascades also play a major role in gut development. These include the Hedgehog, Hh, Bmp, FGF, and Wnt signaling pathways (4,5,6,7,8). They are used at multiple steps of the developmental process. Congenital abnormalities, including malrotations, associate with germline mutations/deletions of genes encoding hedgehog signaling components as reviewed in reference 8.
The endoderm is the precursor to the gastrointestinal epithelial lining, and endodermal development requires the expression of the homeotic genes MIXER, SOX17α and SOX17β (9). Multiple interactions occur between the endoderm, mesoderm, and ectoderm during development. The endoderm induces the mesoderm, conferring on it a dorsal–ventral pattern. Endoderm and ectoderm contact one another in the 2- to 4-week embryo, with the endoderm forming the yolk sac roof. This contact results in up-regulation of growth factors, including transforming growth factor (TGF)-α, TGF-β, epidermal growth factor (EGF), and hepatocyte growth factor (HGF), all of which stimulate cell proliferation. A primitive gut forms in the third to eighth weeks secondary to cephalocaudal and lateral foldings that incorporates the dorsal endodermally lined yolk sac cavity. The amnion and yolk sac communicate through the neuroenteric canal (Fig. 6.1). The neuroenteric canal closes and the notochord grows forward, becoming intercalated within the endoderm. The neural tube then separates from the ectoderm. Mesoderm surrounds the notochord, separating the ectoderm and endoderm (10). (Gastrointestinal duplications associate with a defective spinal cord and/or vertebra if mesodermal ingrowth does not occur and neural and gastrointestinal elements fail to separate.) Splanchnic mesoderm surrounding the primitive gut forms the muscular and connective tissue layers. The former yolk sac elongates under the developing nervous system to form the primitive foregut anteriorly and the primitive hindgut posteriorly. The central portion develops into the midgut, which has a free communication with the yolk sac (the vitellointestinal duct). The anterior abdominal wall develops by simultaneous cranial, caudal, and lateral infoldings, which attenuate the yolk sac, causing it to become intracoelomic in location (Fig. 6.1). The foregut is short at first, lying closely apposed to the developing vertebrae, and it becomes suspended by a short mesentery. The foregut gives rise to the esophagus, stomach, duodenum as far as the ampulla of Vater, liver, pancreas, and respiratory system, and it has its own arterial blood supply deriving from the celiac axis (11).