Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas

Abstract

The generation of the pancreas and small intestine from the embryonic gut depends on intercellular signalling between the endodermal and mesodermal cells of the gut. In particular, the differentiation of intestinal mesoderm into smooth muscle has been suggested to depend on signals from adjacent endodermal cells. One candidate mediator of endodermally derived signals in the embryonic hindgut is the secreted protein Sonic hedgehog (Shh). The Shh gene is expressed throughout the embryonic gut endoderm with the exception of the pancreatic bud endoderm, which instead expresses high levels of the homeodomain protein Ipf1/Pdx1 (insulin promoter factor 1/pancreatic and duodenal homeobox 1), an essential regulator of early pancreatic development. Here, we have examined whether the differential expression of Shh in the embryonic gut tube controls the differentiation of the surrounding mesoderm into specialised mesoderm derivatives of the small intestine and pancreas. To test this, we used the promoter of the Ipf1/Pdx1 gene to selectively express Shh in the developing pancreatic epithelium. In Ipf1/Pdx1-Shh transgenic mice, the pancreatic mesoderm developed into smooth muscle and interstitial cells of Cajal, characteristic of the intestine, rather than into pancreatic mesenchyme and spleen. Also, pancreatic explants exposed to Shh underwent a similar program of intestinal differentiation. These results provide evidence that the differential expression of endodermally derived Shh controls the fate of adjacent mesoderm at different regions of the gut tube.

Pancreas organogenesis: From bud to plexus to gland

“…Removal of notochord causes ectopic Shh expression in the dorsal pancreatic anlagen and perturbs dorsal pancreas development. This early block in pancreas development was probably a consequence of altering the dorsal pancreatic mesenchyme towards a more intestinal quality (Apelqvist et al, 1997;Kim et al, 1997;Hebrok et al, 2000). As will be discussed later, dorsal pancreatic mesenchyme is an important signaling tissue that allows proliferation and morphogenesis of pancreatic progenitors after the initial budding of the anlage.…”

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…Studies in chicken and mice have demonstrated that ectopic expression of Shh during early development results in a loss of Pdx1 expression (and other pancreatic β-cell markers), and in the transformation of pancreatic mesenchyme into duodenal mesenchyme [29] [30]. In addition, continued expression of hedgehog proteins (Shh and Indian hedgehog, Ihh) after initial pancreas formation (at about E12.5 in the mouse) result in reductions in pancreatic mass, including both acinar and endocrine tissues [31].…”

Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

“…During early endoderm differentiation, both Shh and Ihh are expressed strongly throughout the endodermal epithelium, with the exception of pancreatic primordia [4][5][6]. Similarly, Ptch1 is expressed in the mesenchyme adjacent to the pancreas, but expression has not been confirmed in the pancreas area of mouse embryos before embryonic day (E) 12.5 [4].…”

“…Similarly, Ptch1 is expressed in the mesenchyme adjacent to the pancreas, but expression has not been confirmed in the pancreas area of mouse embryos before embryonic day (E) 12.5 [4]. Thereafter, the developing tissue starts to express several HH components [7,8].…”

“…Several groups have investigated the effect of increased HH signalling on pancreatic morphogenesis. Ectopic expression of SHH under the control of the Pdx1 promoter results in almost complete organ ablation [4,12]. In addition, ectopic expression of both SHH and IHH under the control of the Pax4 promoter induces a decreased pancreatic mass [12].…”