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ヘッジホッグ シグナル伝達経路

The Hedgehog (Hh) signaling pathway controls numerous processes during fly and vertebrate embryonic development and adult homeostasis, including tissue/organ patterning, cellular proliferation and differentiation, pathfinding, left / right asymmetry, and stem cell maintenance.There are three known members of Hedgehog protein family: Desert hedgehog homolog (Dhh), Indian hedgehog homolog (Ihh), and Sonic hedgehog (Shh).

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ヘッジホッグ シグナル伝達経路 Background

The Hedgehog (Hh) signaling pathway controls numerous processes during fly and vertebrate embryonic development and adult homeostasis, including tissue / organ patterning, cellular proliferation and differentiation, pathfinding, left / right asymmetry, and stem cell maintenance. Hedgehog (Hh) signaling is dysregulated in several congenital defects and many types of tumors. Hedgehog (Hh) is able to signal at short-range but also may act as a long-range morphogen in multiple contexts (this aspect is controlled in part by lipid modification of the Hh molecule). Hedgehog (Hh) signaling controls the balance of the transcriptional activator and repressor forms of Ci / Gli, the ratios of which are essential for interpreting the level of Hh signal in a morphogenetic field and for generating diverse outputs. There are three known members of Hedgehog protein family: Desert hedgehog homolog (Dhh), Indian hedgehog homolog (Ihh), and Sonic hedgehog (Shh). Desert hedgehog homolog (Dhh) expression is largely restricted to gonads, including sertoli cells of testis and granulosa cells of ovaries. Indian hedgehog homolog (Ihh) is specifically expressed in a limited number of tissues, including primitive endoderm, gut, and prehypertrophic chondrocytes in the growth plates of bones. Approximately 50% of Ihh−/− embryos die during early embryogenesis due to poor development of yolk-sac vasculature. Surviving embryos display cortical bone defects as well as aberrant chondrocyte development in the long bones. Sonic hedgehog (Shh) is the most broadly expressed mammalian Hedgehog (Hh) signaling molecule. During early vertebrate embryogenesis, Sonic hedgehog (Shh) expressed in midline tissues such as the node, notochord, and floor plate controls patterning of the left-right and dorso-ventral axes of the embryo. Sonic hedgehog (Shh) expressed in the zone of polarizing activity (ZPA) of the limb bud is also critically involved in patterning of the distal elements of the limbs. Later in development, during organogenesis, Sonic hedgehog (Shh) is expressed in and affects development of most epithelial tissues.

Hh-Responding Signaling Pathway

Hedgehog (Hh) elicits transcriptional responses by binding to its trimeric receptor Patched (Ptc / Ptch1). When the Sonic Hedgehog (Shh) binds to its Patched (Ptch1) receptor, the Smo repression is alleviated, allowing its translocation from endosomes to the cell surface in flies or to the primary cilium in mice. Flies and vertebrates may use different strategies downstream of Smo to modulate activity of the Ci / Gli transcription factors. Ci / Gli transcription factors are ubiquitinated by Cullin (Cul3) and HIB / SPOP complexes; the expression of Hh-binding proteins, such as Ptc and Hhip1, is upregulated to serve as a sink for extracellular ligand.

Hh-Nonresponding Signaling Pathway

In the absence of Hedgehog (Hh) ligand, Ptc inhibits Smo and prevents its translocation to the cell surface in flies or to the primary cilium in mice. In fly, microtubule-associated Cos-2 serves as a scaffold for protein kinase A (PKA), casein kinase I (CKI), and glycogen synthase kinase 3 (GSK3), which phosphorylate Ci. The SCF-Slimb-Cul1-Roc1a complex recognizes phosphorylated Ci and targets it for proteasome-dependent limited proteolysis, which removes C-terminal transcriptional activation domains to inhibit the downstream gene transcription.

ヘッジホッグ シグナル伝達経路 References

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  3. Sisson JC, et al. (1997) Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell. 90(2): 235-45.
  4. Katoh Y, et al. (2006) Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review). Int J Mol Med. 18(6): 1019-23.