Disease relevance of Ihh

• We show that this ossification defect is not attributable to a permanent arrest in cartilage differentiation, since Ihh(-/-) chondrocytes undergo hypertrophy and terminal differentiation, express angiogenic markers such as Vegf, and are invaded, albeit aberrantly, by blood vessels [1].
• This study examined whether SHH, 2 other ligands IHH and Desert hedgehog, and receptors or downstream targets are expressed in normal gastric epithelium or in intestinal and diffuse-type gastric cancers [2].
• Expression of PTHrPR* in chondrocytes of Ihh(-/-) mice prevented premature chondrocyte hypertrophy but did not rescue either the short-limbed dwarfism or decreased chondrocyte proliferation [3].
• We observed no overt epidermal morphogenesis phenotype in response to Ihh overexpression, however Dhh overexpression resulted in a range of embryonic and adult skin manifestations indistinguishable from Shh overexpression [4].
• A mutation in EXT genes may result in an abnormal Ihh diffusion pattern leading to an osteochondroma [5].

High impact information on Ihh

• Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus [6].
• Indian hedgehog (encoded by Ihh) has been shown to be expressed in the uterine epithelium under the control of the steroid hormone, progesterone [6].
• Smo and Shh/Ihh compound mutants have identical phenotypes: embryos fail to turn, arresting at somite stages with a small, linear heart tube, an open gut and cyclopia [7].
• Reduced Indian hedgehog (Ihh) expression was observed in prehypertrophic chondrocytes, and apoptosis was inhibited in hypertrophic chondrocytes [8].
• Ihh induces the expression of a second signal, parathyroid hormone-related protein (PTHrP), in the periarticular perichondrium [9].

Biological context of Ihh

• The existence of such a repressor provides a window into the distant past, revealing that Shh and Ihh must once have shared responsibilities in establishing tissue boundaries and orchestrating vertebrate tissue morphogenesis [10].
• The significance of these data extends far beyond the field of skeletal biology: they hint at the very real possibility that the endogenous Shh regulatory region contains a repressor designed to segregate the activity of Shh from Ihh [10].
• Bone morphogenetic proteins (BMPs), another family of secreted factors regulating bone formation, have been implicated as potential interactors of the Ihh/PTHrP feedback loop [11].
• In conclusion, the skeletal phenotype of Ihh(-/-) embryos represents the sum of disturbances in three separate cell populations, the chondrocytes, the osteoblasts and the vasculature, each of which is a direct target of hedgehog signaling [1].
• Overexpression of Ihh in the cartilage elements of transgenic mice results in an upregulation of PTHrP expression and a delayed onset of hypertrophic differentiation [11].

Anatomical context of Ihh

• Misexpression of Ihh prevents proliferating chondrocytes from initiating the hypertrophic differentiation process [9].
• In this negative-feedback loop, Ihh inhibits hypertrophic differentiation by regulating the expression of Pthrp, which in turn acts directly on chondrocytes in the growth plate that express the PTH/PTHrP receptor [12].
• In the ex vivo setting, Ihh(-/-) cells differentiate into osteoblasts and deposit a bony matrix, without benefit of exogenous hedgehog in the new environment [1].
• Targeted inactivation of Ihh in mice allows ectopic branching of ventral pancreatic tissue resulting in an annulus that encircles the duodenum, a phenotype frequently observed in humans suffering from a rare disorder known as annular pancreas [13].
• We consider that Ihh has a similar activity to Shh when expressed in the early Shh-responsive limb bud [14].

Associations of Ihh with chemical compounds

• Transcription of Ihh increases dramatically in the luminal epithelium and glands from day 3, reaching very high levels on day 4 [15].
• Transcription of Ihh in ovariectomized mice is induced by progesterone but not by estrogen [15].
• Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus [15].
• Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification [16].
• The ES cell line D3 forms embryoid bodies in suspension culture without addition of retinoic acid and also upregulates Indian hedgehog expression [17].

Physical interactions of Ihh

• Moreover, Runx2 directly bound to the promoter region of the Ihh gene and strongly induced expression of the reporter gene driven by the Ihh promoter [18].

Regulatory relationships of Ihh

• Thus BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or to delay the onset of hypertrophic differentiation [11].
• Adenoviral introduction of Runx2 in Runx2(-/-) chondrocyte cultures strongly induced Ihh expression [18].
• Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development [19].
• Interestingly, Ihh is expressed at the tip of Shh mutant limbs and could account for formation of distal structures [20].
• In the third model in which the PPR was disrupted in about 30% of columnar chondrocytes, Ihh action in the periarticular chondrocytes was upregulated because of ectopically differentiated hypertrophic chondrocytes that had lost PPR [21].
• Dominant-negative Gli2 markedly inhibited Ihh-dependent osteoblast differentiation [22].

Other interactions of Ihh

• A decrease in the domain of transcription of the chondrocyte markers Ihh and PTHrP (Pthlh) corresponded with a decrease in their transcripts in the proliferative and hypertrophic chondrocyte zones [23].
• To determine whether Dbf maps to the Ihh locus, which is also on chromosome 1, we performed an interspecific backcross [14].
• Normally, these cells surrounding the chondrogenic condensation are exposed to IHH, as evidenced by their expression of the hedgehog target genes, patched (Ptch) and Gli1 [1].
• Although bmp6 was expressed, ihh transcripts were not found in primordia of intramembranous bones, nor in cells lining the future articular surfaces [24].
• Rat Dhh mRNA was expressed in prostate, duodenum and dorsal root ganglia, while rat Ihh mRNA was expressed in cartilage [25].

Analytical, diagnostic and therapeutic context of Ihh

• Hh-inactivating monoclonal antibodies or control antibodies were administered to mice that sustained a 50% intestinal resection. mRNA analyses of the preoperative ileum by quantitative real-time PCR revealed that Indian hedgehog was the most abundant Hh family member [26].
• In the present study, we showed by Northern analysis and in situ hybridization that Smoothened (Smo), a key component in hedgehog signal transduction, was expressed in chondrocytes in both adult mice and mouse embryos at 16 days post-coitum in vivo, suggesting that Ihh directly acts on chondrocytes [27].
• To reveal the possible function and interaction of these signaling systems we have started to analyze the expression patterns of signaling factors, antagonists, receptors and transducers of these pathways in forelimbs of mouse embryos and compared them to the expression of established markers including Ihh [28].
• RT-PCR analysis of blastocyst outgrowth cultures demonstrates that whereas little or no Indian hedgehog message is present in blastocysts, significant levels appear upon subsequent days of culture, coincident with the emergence of parietal endoderm cells [17].
• Using EC and ES cell culture to study early development: recent observations on Indian hedgehog and Bmps [29].

References