Endoderm Proteins


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 Endoderm Proteins Background

Evolution of the endoderm

The Animal Kingdom is defined as the collection of multicellular eukaryotes that lack cell walls. One of the first distinct features of animals, shared by nearly all phyla, is the distinction of inner cells and outer cells. These inner cells, defined as endoderm, specialize in activities related to acquiring and processing sustenance for the organism. The most divergent animals from humans to possess an invaginated gut and thus endoderm are cnidaria such as the hydra.

The next major evolutionary step in gut evolution occurred upon acquisition of a through gut with a distinct mouth and anus, which occurs in roundworms. Whether the common opening became the mouth or anus or whether the opening merely became elongated and split has been the subject of numerous hypotheses. Recent evidence examining gene expression from acoelomic organisms, which possess a single opening, suggests that the acoel opening shares gene expression with the roundworm mouth and that gene expression characteristic of roundworm anus is associated with a non-endodermal structure, the gonopore. While the evolutionary process leading to a through gut is hazy, the ability to separate food from waste and the associated opportunity to specialize function along the length of the gut provide clear benefits.

More recent evolutionary innovations have given rise to the structure and function of the vertebrate endoderm. As animals became too thick for all cells to exchange gas directly with the external environment, the endoderm took on a role in respiration. A collection of segments in the anterior endoderm known as the pharyngeal arches, which contribute to the gills in fish and the pharynx of land vertebrates in addition to several other organs including the thyroid, parathyroid, and thymus, emerged at least as early as the divergence of chordates. An air-filled organ capable of gas exchange, potentially homologous to vertebrate lungs, has been noted in the predecessor to fish, the placoderm, although the structure was lost in many descendants of this species.

Additionally, segments of the directional gut were progressively specialized to allow for more efficient ingestion, digestion, absorption and excretion. This progression culminated with the emergence of specialized organs aiding digestion. Chief among these are the liver and pancreas, which share an evolutionary origin in the mollusk hepatopancreas, an organ separated from the linear gut and involved in storage, metabolism, and enzyme secretion. One key role of vertebrate endoderm has been co-opted from the ectoderm. The many endocrine hormones including insulin, glucagon and somatostatin that are secreted by the gut into the circulation in order to regulate metabolism are found only in the brain of insects but are secreted by scattered gut cells of early chordates such as amphioxus. These scattered cells form clusters in Agnatha such as lampreys, and pancreatic islets are found in Chondrichthyes such as sharks.

Compared to the nervous system, which has gained enormous complexity during evolution to more complex organisms, the endoderm has changed little over evolutionary time. Some aspects of the endoderm are tailored to the behavior of particular species, including the transition from gills to lungs upon adaptation to land and the stomach adaptations that permit grass digestion in ruminants. As a whole though, the gut of a frog is strikingly similar to that of a human, suggesting that the developmental mechanisms responsible for giving rise to the mature gut are relatively ancient.

 

Early mammalian development

In order to understand how the mammalian gut is formed during development, it is helpful to review development starting from the blastocyst stage. The blastocyst forms at embryonic day 3.5 (E3.5) of mouse development after successive cleavage divisions of the fertilized egg. Such divisions give rise to the round morula, which begins to develop a cavity called the blastocoel. The inner cell mass, which gives rise to all eventual embryonic lineages, forms a clump of cells on one side of the blastocyst surrounded by trophoblast, which will contribute to the placenta. During the blastocyst stage, salt-and-pepper asymmetric gene expression patterns of the transcription factors Nanog and Gata6 can be detected in inner cell mass cells. Through signaling through the Grb2-MAPK pathway and differential adhesion, these cells segregate by E4.5 into the epiblast, which gives rise to the embryo proper, and the primitive endoderm, a layer of cells covering the inner cell mass in a crescent. The primitive endoderm will give rise to the extraembryonic endoderm lineages, the visceral and parietal endoderm, which play vital roles in nutrient absorption and regulation and help to pattern the embryo during development.

The presence of cells referred to as endoderm prior to gastrulation, especially cells that defy the definition of endoderm and are never found on the inside of an embryonic structure, has caused confusion. Adding to the confusion, gene expression in these cells overlaps significantly with that in definitive endoderm cells. There is some data from fate mapping and more recently from lineage tracing using extraembryonic-restricted Transthyretin and Alpha fetoprotein promoters that extraembryonic endoderm cells contribute to definitive endoderm of the embryo proper, although their contribution is minor. However, the vast majority of the gut forms from the definitive endoderm, which forms during gastrulation.

Gastrulation begins at E6.5 after the blastocyst has extended into an egg-shaped structure. The mechanisms underlying gastrulation have been extensively studied in vertebrates. The first morphological sign of gastrulation is the primitive streak. As in other vertebrates, the mouse primitive streak contains organizer activity, the ability to induce a new axis when transplanted ectopically. However, organizers from different stages of mice possess different degrees of axis-forming ability, and ablation of the node, the late primitive streak organizer, does not affect anterior-posterior patterning. Evidence exists as well for a role for anterior visceral endoderm in anterior patterning, although it does not possess classical organizer activity. Thus, axial patterning during mammalian gastrulation is distributed among a variety of patterning centers.