Here we use a conditional allele of Rac1, the only Rac gene expressed early in development, to define its roles in the gastrulating mouse. At the end of gastrulation, the endoderm is phenotypically homogenous until .. Pascal De Santa Barbara, IGH, Institut de génétique humaine CNRS: UPR .

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The gastrointestinal tract develops from a simple tube to a complex organ with patterns of differentiation along four axes of asymmetry. The organ is composed of all three germ layers signaling to each other during development to form the adult structure.

The gut epithelium is a constitutively developing tissue, constantly differentiating from a stem cell in a progenitor pool throughout the life of the organism. Embryonically important patterning factors are used during adult stages for these processes. Such critical pathways as the gastrulatkon, bone morphogenetic protein, Notch, SOX, and WNT systems are used both in embryologic and adult times of gut development.

We will focus and review the roles of these factors in gut epithelial cell development and differentiation. This review summarizes advances in the understanding of the molecular control of intestinal epithelial cell differentiation.

Recently some elegant multi-disciplinarily studies humaie been published that progress our understanding of endoderm development, intestinal epithelium differentiation, and its homeostasis [ 1 — 7 humainee.

Different molecular pathways and transcription factors have been described and studies in these processes. In order to clarify this review, we have decided to focus on events that we have studied and the pathways that are best understood developmentally. Many of these systems are best known as critical control factors in general body plan developmental processes as well as role in organ pattern formation including having key roles in gastrointestinal development.

These developmentally critical pathways continue to be important in cell differentiation, homeostasis, and apoptosis in the adult intestinal epithelium. Understanding these pathways and how they may interact should provide insight to diseases found associated with gastrointestinal morphogenic defects and epithelial differentiation perturbations.

The vertebrate gastrointestinal tract GI tract is a remarkably complex, three dimensional, specialized and vital organ system derived from a simple tubal structure. GI derivates essentially bud off ventrally from the early gut endoderm and will form the thyroid, lungs, and gastru,ation.

The pancreas develops from the fusion of distinct dorsal and ventral diverticula that originally arise from the gut endoderm posterior to the stomach. The gut is composed of the three germ layers – endoderm which forms the epithelial lining of the lumenmesoderm which forms the smooth muscle layersand ectoderm which includes the most anterior and posterior luminal digestive structure and the enteric nervous system. Morphologic GI tract development has been found to be very similar in all vertebrate species studied.

At the end of gastrulation, the endoderm is phenotypically homogenous until morphogenetic movements occur in cranial and caudal areas. The vertebrate gut tube develops from two ventral invaginations, one at the anterior anterior intestinal portal, AIP and the other at the posterior caudal intestinal portal, CIP end of the embryo.

These invaginations elongate in the endodemal layer and fuse in the midline of the embryo to form a straight tube. During this process lateral plate derived splanchnic mesoderm surrounds the endoderm.

Later in gut development, neural crest derived cells migrate into and colonize the gut to form the enteric nervous system ENS. The ENS arises from the neural crest cells that delaminate from the dorsal region of the neural tube and colonize the whole gut to establish its innervation [ 89 ]. Regional specific morphologic development and differentiation along the anterior-posterior AP axis will give rise to the formation of three regions: These structures respectively will give rise to the adult gut: The LR axis is relatively evidenced early on, by the characteristic turning and looping of the gut in which the stomach is generally positioned on the left side of the organism and the gut loops in a counterclockwise direction.

The endoderm remains uniform in its morphology undifferentiated appearing stratified cuboidal cells throughout all axes of the gut until midgestation in most vertebrates when epithelial-mesenchymal EM interactions direct endodermal differentiation fig.

Finally the endoderm differentiates from signals provided by the mesoderm directed by its AP and DV specific location. The mature adult gut has a morphologic and functional pattern clearly gastrulwtion in all four axes. From development to differentiation of the intestinal epithelium. During early embryonic development, the visceral endoderm appears uniform and presents stratified cell layer. Intestinal epithelial cytodifferentiation occurs during foetal development and is marked by mesodermal growing into gqstrulation lumen and villi formations.


These villi are separated by proliferative intervillus epithelium. AP axis differences appear and are characterized by long and thin villi in the small intestine and by transitory wide and flat villi in the colon. Humainee intervillus epithelium of the small intestine is reshaped downward forming crypts. In human, final architecture of the small intestine is reached before birth and is characterized by the crypt-villus unit. Hymaine colonic villi disappeared at the time of birth and the mature colonic epithelium present tubular glands crypts.

GASTRULATION – Definition and synonyms of gastrulation in the French dictionary

Genetic controls of endoderm development have been less well studied as the mesoderm or ectoderm [ 10 ]. Numerous factors involved in the specification of the endoderm layer have been described and reviewed for review see [ 11 ]. Other factors, such as Sox17, first have been identified as early endodermal specification factors, but also its action during gut endoderm development was recently demonstrated [ 1213 ]. SOX genes have been identified as key players in numerous developmental processes: SOX genes are also involved in pathologic development as well [ 20 ] shown to be involved in pathways controlling cellular proliferation [ 21 ] and oncogenesis [ 22 ].

Early endoderm formation is under control of Sox17 expression as demonstrated in Xenopus [ 1223 ]. Recently in zebrafish, casanova, a novel member of SOX family gene acts upstream of zebrafish Sox17 related gene and as Sox17 is sufficient to induce early endodermal formation [ 24 — 28 ].

Murine knockouts for Sox17 show that Sox17 is essential for embryonic cells to acquire endodermal cell fate but also suggests a potential redundancy with other SOX gene expressed on overlapping endodermal territory [ 13 ].

Disruption of Sox 17 gene in the murine system has an impact on endoderm development but does not affect the formation of the anterior definitive endoderm [ 13 ]. Published and unpublished observations have demonstrated the presence of at least 5 different SOX genes expressed in the gut endoderm: Sox2 [ 29 ], Sox7 [ 3031 ], Sox9 P.

Additive functions of SOX genes in intestinal epithelium are suggested by different expressional studies [ 31 — 33 ]. Moreover, in our experiments we shown that SOX9 expression changes during the differentiation state of the intestinal epithelium, with restriction of then along villi axis, indicating a potential function of SOX gene during the epithelial differentiation process P.

Hox genes are homeobox containing transcription factors conserved across divergent species [ 3435 ]. Hox genes function in pattern formation of many aspects of development including the overall body plan [ 3637 ], limb [ 38 ], CNS [ 3940 ], and viscera [ 41 — 44 ]. Mesodermal expression of specific Hox genes play an important role in patterning the gut along the AP axis in both the gross morphology of the gut and later the epithelial-mesenchymal interactions responsible for normal gut epithelial differentiation [ 4245 ].

These vertebrate Hox genes are expressed spatially in the most posterior body regions and subregions [ 41 ].

In the gut, these Hox genes are expressed in a spatially and temporally specific manner in the posterior mesoderm of the gut, from the post-umbilical portion of the midgut through the hindgut [ 41 — 4345 ].

Hoxa13 and Hoxd13 are co-expressed in the distal most hindgut mesoderm anorectal mesoderm in the mouse and cloacal gastrulatin in the chick gastrhlation uniquely throughout the hindgut endoderm [ 4246 ].

The tissue specific roles of these genes were not dissected. Were the anomalies seen in the null mice due to absence of Hox function in the mesoderm, the endoderm, or both?

Recently, the role of Hoxa13 in the posterior endoderm was investigated using the avian system.

Meaning of “gastrulation” in the French dictionary

A Hoxa13 mutant protein, which behaves as a dominant-negative, was specifically expressed in the early developing chick posterior endoderm [ 45 ]. This was the first time that a specific endodermal function of a Hox gene was described.

Different Hox genes also were found expressed in the small and large intestine endoderm, such as Hoxa8however no functional studies were made [ 4748 ]. Their expressions let us hypothesize specific functions of intestinal endodermally expressed Hox genes, but still to be described.


Hox gene expression is principally mesodermal in the gut, and expression occurs early in gut development, before any pattern formation in the 4 axes is evident. We have previously shown that Hoxd13 and Hoxa13 have a function in the mesoderm to direct differentiation of the overlying endoderm [ 4245 ]. Both Hoxd13 and Hoxa13 are expressed in the distal most hindgut mesoderm [ 414346 ].

Both are also expressed in the entire hindgut endoderm [ humzine ]. These put Hoxd13 and Hoxa13 as players in the hindgut mesoderm to endoderm signaling that has been hummaine to direct the final epithelial phenotype.

Recently, the mesodermal-endodermal HOX crosstalk pathway was also observed in mouse [ 49 ] and shows a strong conserved function of Hox genes in GI tract differentiation. The Hedgehog Hh pathway in Drosophila and vertebrates is conserved and known to play an important role in gut development [ 50 — 52 ]. Sonic hedgehog Shh is an important factor implicated in the first phase of EM signaling in the gut [ 4153 ].

As the gut tube forms and undergoes morphogenesis, Shh expression expands gsstrulation is maintained in the gut endoderm with the exception of the GI tract derivates [ 56 — 58 ]. One other member of the Hh family, Indian hedgehog Ihhis expressed later in the gut endoderm in a partially overlapping pattern [ 1 ]. The gastrupation of Hh signaling in the early gut endoderm layer is not well defined, but its action in the adjacent mesoderm was demonstrated.

Endodermally secreted Shh acts via its mesodemal expressed receptor Patched Ptc to induce mesodermal expression of Bmp4 [ 4142 ]. Early endodermal Shh humaone was suggested to act as a signal in epithelial-mesenchymal interaction in the earliest stage of hindgut formation [ 41 ].

BMP ligands were initially identified as regulators of bone formation [ 59 ], but subsequent analyses have suggested that these ligands regulate a spectrum of developmental processes throughout embryogenesis and organogenesis reviewed gwstrulation [ 60 ].

These data suggest an unexpected and early role of BMP signaling in the development and patterning of the endodermal AIP structure formation.

Recent investigations have gasyrulation the roles of BMP in patterning the gut during development. Bmp-4 is expressed throughout the mesoderm of the chick gut sparing expression only in the vastrulation muscular stomach gizzard [ 426465 ].

Retroviral misexpression experiments suggest that level of BMP activity may have fundamental roles in the control of gut muscular development, in the pyloric sphincter development, and in the gaetrulation gland formation [ 4264 — 67 ].

Endogenous activation of this pathway is specifically found in the gut mesenchyme layer but also in the developing endoderm. The function of the BMP pathway humaune early gut endoderm is still unknown. Later in gut development, some roles gasturlation the pathway have yumaine suggested see below. The intestinal endoderm layer forms the intestinal characterized in the RAD axis with the establishment of the villus-crypt axis. The pseudostratified endoderm formed of undifferentiated cells undergoes a columnar transformation accompanied with a mesodermal outgrowth.

This process results in the development of structures termed villi, which form along a cranial to caudal wave fig. AP axis influences the RAD axis in morphologic and epithelial cellular differentiation. In late fetal life, small intestine epithelium is characterized by long and thin villi, whereas colon epithelium shows wide and flat villi.


These villi are separated by a proliferating intervillus epithelium fig. As the gut develops the intervillus epithelium is reshaped downward forming crypts.

The crypt villous unit humaie for a great increase gastrulafion surface area for absorption. Small intestines conserve their villus-crypt unit throughout life fig. In many species, including human but not in chick the embryonic villi will be lost in adult colonic epithelium.

Human colon has a relatively flat epithelium separated regularly by crypts fig. The formation of these crypt-villous structures and epithelial cellular differentiation relies on reciprocal signaling between the endoderm and mesoderm EM for review see [ 68 ]. The function of small intestine epithelium is digestion and absorption of nutrient. Therefore, the epithelial cells are highly specialized and metabolically active.