In birds and mammals, the endoderm is a disk that invaginates, starting at its anterior and posterior ends, to form a closed epithelial cylinder surrounded by a thin layer of splanchnic mesoderm. The splanchnic mesoderm later becomes smooth muscle. The endoderm gives rise to the pancreas, liver and lungs via branching of endodermal tubes. Regional morphological differences amongst epithelial cells demarcates the three endodermal segments, each of which evaginate:
|Foregut||The most anterior region of the foregut broadens and becomes the pharynx. The lateral sides evaginate, forming pharyngeal pouches which give rise to: gill slits (fish and amphibians) or part of the jaw, ear and neck (reptiles, birds and mammals). The esophagus forms as a dorsal extension of the pharynx. At its posterior end, the esophagus widens into the stomach. At its anterior end, the esophagus forms a lung bud (aka tracheal bud) that gives rise to lungs in a manner similar to hepatic (liver) and pancreatic development.|
|Midgut||The midgut becomes the small intestine. Epithelium develops finger-like outgrowths called villi. Villi hugely expand the gut's surface area, thus aiding nutrient absorption. Between villi, the epithelium sinks to form crypts. The foregut and hindgut also form crypts, but lack villi. Undifferentiated endodermal stem cells proliferate at the neck of each crypt (the proliferation zone). Enterocytes (absorptive cells) migrate into the villi as they differentiate. Gland cells migrate deeper into the crypt as they differentiate. This polarized pattern is maintained throughout life. In the anterior of the midgut, hepatic and pancreatic buds arise; these will form the liver and pancreas, respectively.|
Regulation of the constant rapid division in the intestine is import to avoid cancer. Intestinal cell differentiation depends on Cdx2 expression. If cells do not differentiate correctly, they continue to proliferate. As expected, Cdx2+/- knockout mice develop colon tumors at a high rate. Defects in the APC gene (encoding adenomatous polyposis coli or APC) are the most common cause of human colorectal cancer. APC targets β-catenin for degradation; β-catenin interacts with TCF/LEF factors in the Wnt signaling pathway, which maintains stem cell proliferation. APC defects reduce β-catenin degradation, causing excessive Wnt signaling and thus overabundant proliferation. Similarly, colorectal cancers sometimes arise from mutations that stabilize β-catenin or increase TCL/LEF factor levels.
What controls A/P Patterning of endodermal organs?
Hox genes are expressed collinearly along the antero-posterior axis in the endoderm and mesoderm. Distinct Hox expression domains oft coincide with distinct intestinal domains. This is reminiscent of Hox gene expression in morphologically distinct rhombomere and somite units. However, Hox deletions generally cause malformations (instead of homeotic transformations) in the intestine.
For example, Hoxa5-/- mutants (expressed in mesoderm around the outgrowing tracheal bud) have small trachea and lungs. Hox13-/- mutants (the most posteriorly restricted Hox gene) have cloaca (hindgut) and anal sphincter defects. Hox mutations impact tissues at the anterior boundary of the Hox gene's expression -- as in rhombomeres and somites, this is called posterior prevalence.
The mechanism that restricts Hox gene expression to specific antero-posterior levels of the endodermal tube is unknown. In some cases, Shh has been shown to act as an inducing signal controlling Hox gene expression. This may explain why Shh mutants exhibit transformations in identity of endodermal organs along the A/P axis. FGFs produced in the lateral plate mesoderm may also be involved.
ParaHox is a complex of three homeodomain genes also expressed sequentially along the antero-posterior axis that reflects their chromosomal order. Of these three genes (Cdx, Pdx and Nkx in vertebrates), Caudal is the most posteriorly expressed ParaHox gene. Vertebrate Cdx-/- mutants have posterior gut defects; Drosophila, Caudal-/- mutants flat-out lack a posterior gut. Caudal thus has a conserved role in posterior gut development.
Other ParaHox genes are also required for endoderm development. Pdx1 expression is induced in the region of the midgut endoderm that has the potential to develop into pancreas before any overt sign of pancreatic bud formation. Pdx expression persists in the pancreatic bud once it has formed. Nkx2.1 is expressed in the ventral foregut region. It is required for the lung and thyroid, both ventral invaginations of the foregut endoderm.
What signals and tissues control formation of pancreas vs. liver?
The pancreas and liver develop as buds (invaginations) at the same antero-posterior location. However, they are on opposite sides of the endodermal tube. Adjacent tissues secret signals to induce the endoderm into liver or pancreas. The dorsal mesoderm is closest to the notochord. The notochord secretes TGFβ and chordin, reducing Shh activity in the dorsal mesoderm. This reduced Shh activity (via notochord signals) initiates its differentiation as pancreas. The ventral mesoderm is furthest from the notochord. It therefore has high Shh activity. Also, adjacent cardiac mesoderm secretes BMPs. Shh and BMP induce the ventral mesoderm to differentiate as liver.
In other words, BMP and Shh induce the ventral mesoderm to differentiate as liver. The BMP is secreted by adjacent cardiac mesoderm. Low Shh activity induces the dorsal mesoderm to differentiate as pancreas. Shh activity is reduced by TGF-β and chordin secretions by the adjacent notochord.
Different tissues control pancreas development at different times. Pancreas development is initiated by chording and TGF-β secreted by the notochord. Later, the aorta forms between the notochord and prospective pancreas. The aorta secretes signals to continue pancreas development.
The mature pancreas is derived from dorsal mesoderm. It contains endocrine and exocrine cells. Endocrine cells (aka β cells) produce insulin to stimulate glucose uptake by cells. Exocrine cells produce amylase, a digestive enzyme. Type I diabetes arises from a loss of β cells. Different transcription factors specify immature pancreatic cells as β or exocrine cells. Endoderm → Pancreatic cells (by Pdx1, Ptf1a) → Exocrine cells (Ptf1a) and β cells (Ngn3).
Describe proliferation vs differentiation in intestinal villi.
Describe the role of the Wnt pathway in intestinal stem cells.
Intestinal vili are self-renewing epithelium. Deep Cyrpts of Lieberkühn (aka Crypts) contain, from the bottom of the crypt up to its cusp: slowly dividing stem cells; rapidly dividing stem cells; enteroendocrine cells; gobelet cells; and enterocytes. Cells migrate up out of the crypt to the very tips of the vili, where they shed away to make room for new cells.
β-catenin is required for stem cell proliferation in the intestine. In the deep crypt are proliferating undifferentiatd precursors; β-catenin/TCF is activatedhere. At the crypt's rim are nonproliferating differentiated cells; β-catenin/TCF is turned off. BMPs and other secreted signals promote differentiation.
Wnt signaling blocks the GSK/APC complex from degrading β-catenin. Thus, Wnt signaling stabilizes β-catenin and maintains stem cells. Wnt-/-, β-catenin-/-, TCF-/- and LEF-/- mice have defective stem cell proliferation and thus few and shorter or even no intestinal vili. Wnt → Stabilized β-catenin → β-catenin + TCF/LEF in Nucleus → Wnt-Regulated Genes.
What is the relationship between the Wnt pathway and colorectal cancer?
One of the leading causes of death in the US (2nd leading cause of cancer-related death). Mutations in the Wnt signaling pathway that lead to high levels of TCF/LEF activity are responsible for most cases of colorectal cancer in humans.
Colorectal patients with Wnt signaling mutations frequently have an overactive Wnt that essentially ablates APC, allowing for permanent β-catenin activation. This causes over-proliferation of stem cells. Also, mutant β-catenin may be resistant to degradation.
How is the position of cells along the apical basal axis of the villus determined?
Ephrin signaling controls localization of differentiated cells in villi (cell sorting).
What Is Branching Morphogenesis? What Is the Role of FGF10 and Shh?
What Is the Relationship Between Drosophila Tracheal Branching Morphogenesis and Lung Branching?
What Factors Control Tracheal Branching in Drosophila?
Respiratory systems form via branching morphogenesis. The laryngotracheal groove is a respiratory diverticulum (an outgrowth) that emanates via invagination from the foregut. This area of the foregut forms the pharynx, posteriorly it develops into esophagus. In vertebrates, the trachea forms two lung buds at its posterior end. Localized ECM breakdown (by hyaluronidase secretion) at tips of growing buds lets branches burst through.
In Drosophila, Branchless encoded FGF and Breathless encoded the FGF receptor. Branchless is expressed around tracheal primordium in advance of in advance of outgrowth. Cells at the tip of the tracheal bud grow filopodia. FGF expression is downregulated by Sprouty (Drosophila) and Shh (vertebrates). FGF-/-, Sprouty++++++ and Shh++++++ mutants have unbranched tracheal buds.
What Is the Role of the Node in Left/Right Asymmetry? What Is the Potential Role of Cilia in Left/Right Asymmetry?
Left/right asymmetry is controlled early in development by Hensen's Node (or just the node). Shh is expressed only on the left side of the node. Shh induces the expression of nodal, a secreted protein, only on the left side of the embryo. If the pattern of nodal expression is made symmetric by implanting a pellet of cells expressing Shh on the right side of the node, then organ asymmetry is lost, and organs are randomly placed in the body.
Cilia located in the node may provide this left-localization of Shh, perhaps by causing a directional flow of signaling molecules. Mutations in left-right dynein (lrd) cause randominzation of organ placement; dyneins are motor proteins that move along microtubules and are involved in cilia movement. Furthermore, individuals with Kartagener's Syndrome (where all cilia are immotile) have random organ placement.