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Evolutionarily conserved developmental pathways

Hox genes and Bmps collaborate in the regionalization of the gut

It has been proposed that the original purpose of Hox genes was to pattern the gut, being co-opted afterwards to pattern other morphological structures such as the skeleton. One might therefore expect that Hox gene function in gut regional patterning will be highly conserved throughout evolution. In that regard, a parallel can be drawn between the anomalies encountered in the gut of Hoxa5–/– mice and those reported in Sex combs reduced Drosophila mutants. Sex combs reduced is the Hoxa5 ortholog and its loss of function leads to the absence of the gastric cecae at the foregut-midgut boundary. scr is also expressed in the posterior part of the midgut, where it may play a role in the formation of the fourth midgut constriction. Both the gastric cecae and the fourth constriction correspond to functional frontiers separating the midgut from the rest of the digestive tract in Drosophila. Analogously in Hoxa5–/– mutants, morphological anomalies are encountered in the regions delimiting the midgut: the stomach and the proximal colon. Although the possibility that the Hoxa5 mutation could interfere with the expression of 5' located Hox genes that could result in colonic anomalies cannot be excluded, the similarity between Hoxa5 and scr expression patterns and function during gut development agrees with a conserved role of this paralog group in the delimitation of functional midgut boundaries (Aubin, 2002 and references therein).

In the Drosophila midgut, the Ultrabithorax gene regulates at the transcriptional level the visceral mesodermal expression of the Bmp4 homolog decapentaplegic. Similar interactions occur in vertebrates. Muscular and submucosal development of the vertebrate stomach also requires Hedgehog signaling. Studies in chick embryos have shown that endoderm-derived Shh inhibits smooth muscle development, resulting in the differentiation of non-muscle layers such as the lamina propria and the submucosa. The analysis of Hh compound mutants also reveals that Ihh and Shh share redundant functions in muscle patterning of the gut. In Hoxa5 mutants, overall Hh signaling is elevated as shown by enhanced Ptc and Gli expression. Therefore, the hypertrophied submucosa observed in Hoxa5–/– stomachs may be a consequence of the increased Hh signaling. Hoxa5 action in establishment of Shh and Ihh gradients necessitates mesenchymally expressed intermediate(s). Bmps have been shown to be important regulators of glandular stomach development. Moreover in several species, a network exists between Hox, Bmp and Hh gut gene expression. For instance, ectopic Shh is able to induce Bmp4 expression in the chick hindgut and in the stomach. Although a complex situation prevails regarding the capacity of Shh to activate Bmp4 expression in foregut derivatives, it has been proposed that Hox genes influence the regionalized response to Shh. Even though the induction of Bmp4 by Shh in the stomach mesenchyme has not been directly addressed in the mouse, the change in the Bmp4 expression pattern observed in Hoxa5–/– stomachs is in agreement with this notion. It is also possible that Hoxa5 directly controls Bmp4 expression in the stomach (Aubin, 2002 and references therein).

In Drosophila Dpp stimulates expression of another extracellular signal, Wingless (Wg), in a neighboring parasegment (ps8), which in turn feeds back to ps7 to stimulate Ubx expression. Thus, Dpp is part of a "parautocrine" feedback loop of Ubx (i.e., an autocrine feedback loop based partly on paracrine action) that sustains its own expression through Dpp and Wg (Eresh, 1997).

Dpp also synergises with Wingless to induce expression of another Hox gene, labial (lab), in the Drosophila gut. In parasegment 7 Dpp spreads to the inner layer of the embryonic midgut, the endoderm, where it synergizes with Wg to induce expression of labial. To achieve this, Dpp locally elevates the endodermal expression levels of Drosophila D-Fos with which it cooperates to induce lab. Differentiation of various cell types in the larval gut depends on these inductive effects of Dpp and Wg (Eresh, 1997). Expression of labial in the midgut coincides with copper cells. Labial has a role not only in determination and differentiation of copper cells, but also in the maintenance of their differentiated state. The function of copper cells may be to adsorb metal ions from the gut lumin (Hoppler, 1994).

date revised: 10 September 2002

Developmental Pathways conserved in Evolution

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