Orchestrating ontogenesis: variations on a theme by sonic hedgehog (original) (raw)
Ingham, P. W. & McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev.15, 3059–3087 (2001). CASPubMed Google Scholar
Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and routers. Science304, 1755–1759 (2004). CASPubMed Google Scholar
Hooper J. E. & Scott, M. P. Communicating with Hedgehogs. Nature Rev. Mol. Cell Biol.6, 306–317 (2005). CAS Google Scholar
Lewis, P. M. et al. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell105, 599–612 (2001). CASPubMed Google Scholar
Gallet, A., Ruel, L., Staccini-Lavenant, L. & Therond, P. P. Cholesterol modification is necessary for controlled planar long-range activity of Hedgehog in Drosophila epithelia. Development133, 407–418 (2006). CASPubMed Google Scholar
Li, Y., Zhang, H., Litingtung, Y. & Chiang, C. Cholesterol modification restricts the spread of Shh gradient in the limb bud. Proc. Natl Acad. Sci. USA103 6548–6553 (2006). CASPubMedPubMed Central Google Scholar
Pepinsky, R. B. et al. Identification of a palmitic acid-modified form of human Sonic hedgehog. J. Biol. Chem.273, 14037–14045 (1998). CASPubMed Google Scholar
Burk, E. R. et al. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell99, 803–815 (1999). Google Scholar
Ma, Y. et al. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell111, 63–75 (2002). CASPubMed Google Scholar
Nakano, Y. et al. Inactivation of dispatched 1 by the chameleon mutation disrupts Hedgehog signalling in the zebrafish embryo. Dev. Biol.269, 381–392 (2004). CASPubMed Google Scholar
Glise, B. et al. Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog. Dev. Cell8, 255–266 (2005). CASPubMed Google Scholar
Gorfinkiel, N., Sierra, J., Callejo, A., Ibanez, C. & Guerrero, I. The Drosophila ortholog of the human Wnt inhibitor factor Shifted controls the diffusion of lipid-modified Hedgehog. Dev. Cell8, 241–253 (2005). CASPubMed Google Scholar
Han, C., Belenkaya, T. Y., Wang, B. & Lin, X. Drosophila glypicans control the cell-to-cell movement of Hedgehog by a dynamin-independent process. Development131, 601–611 (2004). CASPubMed Google Scholar
Yao, S., Lum, L. & Beachy, P. The Ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell125, 343–357 (2006). CASPubMed Google Scholar
Tenzen, T. et al. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev. Cell10, 647–656 (2006). CASPubMed Google Scholar
Zhang, W., Kang, J. S., Cole, F., Yi, M. J. & Krauss, R. S. Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev. Cell10, 657–665. (2006). CASPubMed Google Scholar
Ingham, P. W., Taylor, A. M. & Nakano, Y. Role of the Drosophila patched gene in positional signalling. Nature353, 184–187 (1991). CASPubMed Google Scholar
van den Heuvel, M. & Ingham, P. W. smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. Nature382, 547–551 (1996). CASPubMed Google Scholar
Alcedo, J., Ayzenzon, M., Von Ohlen, T., Noll, M. & Hooper, J. E. The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell86, 221–232 (1996). CASPubMed Google Scholar
Stone, D. M. et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature384, 129–134 (1996). CASPubMed Google Scholar
Bijlsma, M. F. et al. Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol.18, 1397–1410 (2006). Google Scholar
Alexandre, C., Jacinto, A. & Ingham, P. W. Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins. Genes Dev.10, 2003–2013 (1996). CASPubMed Google Scholar
Bai, C. B., Stephen, D. & Joyner, A. L. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev. Cell6, 103–115 (2004). A comprehensive analysis of the development of cell types in the spinal cord inGlimutant embryos, establishing that, in the spinal cord, all HH signalling is GLI dependent. CASPubMed Google Scholar
Wang, B., Fallon, J. F. & Beachy, P. A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell100, 423–434 (2000). CASPubMed Google Scholar
Pan, Y., Bai, C. B., Joyner, A. L. & Wang, B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol. Cell. Biol.26, 3365–3377 (2006). CASPubMedPubMed Central Google Scholar
Bai, C. B., Auerbach, W., Lee, J. S., Stephen, D. & Joyner, A. L. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development129, 4753–4761 (2002). CASPubMed Google Scholar
Briscoe, J. & Ericson, J. The specification of neuronal identity by graded Sonic Hedgehog signalling. Semin. Cell Dev. Biol.10, 353–362 (1999). CASPubMed Google Scholar
Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell75, 1417–1430 (1993). CASPubMed Google Scholar
Krauss, S., Concordet, J. P. & Ingham, P. W. A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell75, 1431–1434 (1993). CASPubMed Google Scholar
Roelink, H. et al. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell76, 761–775 (1994). CASPubMed Google Scholar
Gritli-Linde, A., Lewis, P., McMahon, A. P. & Linde, A. The whereabouts of a morphogen: direct evidence for short- and graded long-range activity of hedgehog signaling peptides. Dev. Biol.236, 364–386 (2001). CASPubMed Google Scholar
Ericson, J., Briscoe, J., Rashbass, P., van Heyningen, V. & Jessell, T. M. Graded sonic hedgehog signaling and the specification of cell fate in the ventral neural tube. Cold Spring Harb. Symp. Quant. Biol.62, 451–466 (1997). During the development of the vertebrate nervous system, distinct classes of motor neurons and interneurons are generated at distinct dorso-ventral positions in the ventral neural tube.In vitrostudies of explanted neural tissue show that the differentiation of these neuronal subtypes is directed by the secreted protein SHH. CASPubMed Google Scholar
Patten, I. & Placzek, M. Opponent activities of Shh and BMP signalling during floor plate induction in vivo. Curr. Biol.12, 47–52 (2002). CASPubMed Google Scholar
Agarwala, S., Sanders, T. A. & Ragsdale, C. W. Sonic hedgehog control of size and shape in midbrain pattern formation. Science291, 2147–2150 (2001). CASPubMed Google Scholar
Hynes, M. et al. The seven-transmembrane receptor smoothened cell-autonomously induces multiple ventral cell types. Nature Neurosci.1, 41–46 (2000). Google Scholar
Briscoe, J., Chen, Y., Jessell, T. M. & Struhl, G. A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube. Mol. Cell7, 1279–1291 (2001). Describes a general method for blocking the transduction of HH signals through ectopic expression of a deleted form of the HH receptor, PTCH1. Expression of the construct causes cell-autonomous ventral-to-dorsal switches in progenitor identity and neuronal fate throughout the ventral neural tube, supporting the hypothesis that SHH functions directly as a long-range morphogen gradient. Expression of the mutant PTCH1 also causes the abnormal spread of SHH to more dorsal cells, indicating that SHH in the neural tube, like HH inD. melanogaster, induces a feedback mechanism that limits its range of action. CASPubMed Google Scholar
Wijgerde, M., McMahon, J. A., Rule, M. & McMahon, A. P. A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. Genes Dev.16, 2849–2864 (2002). By generating mice that are chimeric for SMO-mutant cells, the authors demonstrate that inactivation of SMO causes a cell-autonomous block in the ability of cells to transduce the HH signal. They also show that direct HH signalling is essential for the specification of all ventral progenitor populations, supporting the idea that SHH functions directly and at long range to establish neuronal identity. CASPubMedPubMed Central Google Scholar
Briscoe, J., Pierani, A., Jessell, T. M. & Ericson, J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell101, 435–445 (2000). CASPubMed Google Scholar
Litingtung, Y. & Chiang, C. Specification of ventral neuron types is mediated by an antagonistic action between Shh and Gli3. Nature Neurosci.10, 979–985 (2000). Google Scholar
Persson, M. et al. Dorsal–ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. Genes Dev.16, 2865–2878 (2002). CASPubMedPubMed Central Google Scholar
Lei, Q., Zelman, A. K., Kuang, E., Li, S. & Matise, M. P. Transduction of graded Hedgehog signaling by a combination of Gli2 and Gli3 activator functions in the developing spinal cord. Development13, 3593–3604 (2004). Google Scholar
Matise, M. P., Epstein, D. J., Park, H. L., Platt, K. A. & Joyner, A. L. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Development125, 2759–2770 (1998). CASPubMed Google Scholar
Ding, Q. et al. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development125, 2533–2543 (1998). CASPubMed Google Scholar
Stamataki, D., Ulloa, F., Tsoni, S. V., Mynett, A. & Briscoe, J. A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube. Genes Dev.19, 626–641 (2005). This study uses modified forms of a GLI protein with different levels of transcriptional activation activity to test the hypothesis that graded SHH activity is translated into a gradient of GLI activity. The authors show that small changes in the level of GLI activity can specify alternative neuronal subtypes, which is consistent with the gradient hypothesis. Furthermore, the data suggest that cells integrate the level of signalling over time, which is consistent with the idea that signal duration, along with signal strength, is an important parameter that controls dorsal–ventral patterning in the neural tube. CASPubMedPubMed Central Google Scholar
Dahmane, N. et al. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development128, 5201–5212 (2001). CASPubMed Google Scholar
Lai, K., Kaspar, B. K., Gage, F. H. & Schaffer, D. V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature Neurosci.6, 21–27 (2003). CASPubMed Google Scholar
Charrier, J. B., Lapointe, F., Le Douarin, N. M. & Teillet, M. A. Anti-apoptotic role of Sonic hedgehog protein at the early stages of nervous system organogenesis. Development128, 4011–4020 (2001). CASPubMed Google Scholar
Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature383, 407–413 (1996). CASPubMed Google Scholar
Rowitch, D. H. et al. Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J. Neurosci.19, 8954–8965 (1999). CASPubMedPubMed Central Google Scholar
Goodrich, L. V., Johnson, R. L., Milenkovic, L., McMahon, J. A. & Scott, M. P. Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev.10, 301–312 (1996). CASPubMed Google Scholar
Jeong, J. & McMahon, A. P. Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1. Development132, 143–154 (2005). This paper addresses the significance of feedback systems in SHH-dependent spinal cord patterning. Mouse embryos that lack both PTCH1 and HHIP feedback activities show severe patterning defects that are consistent with an increased magnitude and range of HH signalling. They also show disrupted growth control. CASPubMed Google Scholar
Cayuso, J., Ulloa, F., Cox, B., Briscoe, J. & Marti, E. The Sonic hedgehog pathway independently controls the patterning, proliferation and survival of neuroepithelial cells by regulating Gli activity. Development133, 517–528 (2006). The authors show that blockade of SHH signalling or inhibition of GLI activity results in cell-autonomous decreases in progenitor proliferation and survival. Conversely, positive GLI activity promotes proliferation and rescues the effects of inhibiting HH signalling. In this way, they establish that, as well as specifying neuronal identity, SHH functions directly and at long range to promote the proliferation and survival of neuronal progenitor cells. CASPubMed Google Scholar
Shkumatava, A. & Neumann, C. J. Shh directs cell-cycle exit by activating p57Kip2 in the zebrafish retina. EMBO Rep.6, 563–569 (2005). CASPubMedPubMed Central Google Scholar
Ingham, P. W. & Kim, H. R. Hedgehog signalling and the specification of muscle cell identity in the zebrafish embryo. Exp. Cell Res.306, 336–342 (2005). CASPubMed Google Scholar
Wolff, C., Roy, S. & Ingham, P. W. Multiple muscle cell identities induced by distinct levels and timing of hedgehog activity in the zebrafish embryo. Curr. Biol.13, 1169–1181 (2003). Using a combination of gene knock down of Hh-pathway components and pharmacological inhibition of Smo, the authors providein vivoevidence that Hh signalling acts in a dosage-dependent manner to specify cell fate in the zebrafish myotome; furthermore, they show that Shh induces different muscle cell types at different developmental stages. CASPubMed Google Scholar
Riddle, R. D., Johnson, R. L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell75, 1401–1416 (1993). CASPubMed Google Scholar
Ahn, S. & Joyner, A. L. Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Cell118, 505–516 (2004). CASPubMed Google Scholar
Harfe, B. D. et al. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities Cell118, 517–528 (2004). An elegant use of CRE-LOX-mediated genetic marking to follow the fates of cells that express SHH in the developing limb bud. The data suggest that, although the specification of cells that form the anterior digits depends on the differential concentrations of SHH to which they are exposed, the length of time of exposure to SHH is crucial for the specification of the differences between the cells that form the more posterior digits. CASPubMed Google Scholar
Chen, Y. & Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell87, 553–563 (1996). CASPubMed Google Scholar
Tickle, C. Patterning systems — from one end of the limb to the other. Dev. Cell4, 449–458 (2003). CASPubMed Google Scholar
Niswander, L. & Martin, G. FGF4 and BMP2 have opposite effects on limb growth Nature361, 68–71 (1993). CASPubMed Google Scholar
Scherz, P. J., Harfe, B. D., McMahon, A. P. & Tabin, C. J. The limb bud Shh–Fgf feedback loop is terminated by expansion of former ZPA cells Science305, 396–399 (2004). This study shows that SHH-expressing cells and their descendants cannot express gremlin, a key intermediary that drives limb outgrowth through a SHH–FGF4 loop. The proliferation of these cells forms a barrier that separates the SHH signal from cells that are competent to express gremlin in response to SHH, which breaks down the SHH–FGF4 loop and thereby limits the growth of the limb. CASPubMed Google Scholar
Concordet, J. P. Spatial regulation of a zebrafish patched homologue reflects the roles of sonic hedgehog and protein kinase A in neural tube and somite patterning. Development122, 2835–2846 (1996). CASPubMed Google Scholar
Baxendale, S. et al. The B-cell maturation factor Blimp-1 specifies vertebrate slow-twitch muscle fiber identity in response to Hedgehog signaling. Nature Genet.36, 88–93 (2004). CASPubMed Google Scholar
Park, H. C., Shin, J. & Appel, B. Spatial and temporal regulation of ventral spinal cord precursor specification by Hedgehog signaling. Development131, 5959–5969 (2004). CASPubMed Google Scholar
Takebayashi, H. et al. The basic helix-loop-helix factor olig2 is essential for the development of motoneuron and oligodendrocyte lineages. Curr. Biol.12, 1157–1163 (2002). CASPubMed Google Scholar
Lee, S. K., Lee, B., Ruiz, E. C. & Pfaff, S. L. Olig2 and Ngn2 function in opposition to modulate gene expression in motor neuron progenitor cells. Genes Dev.19, 282–294 (2005). CASPubMedPubMed Central Google Scholar
Zhou, Q., Choi, G. & Anderson, D. J. The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2. Neuron31, 791–807 (2001). CASPubMed Google Scholar
Qi, Y. et al. Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor. Development128, 2723–2733 (2001). CASPubMed Google Scholar
Ingham, P. W. Localized hedgehog activity controls spatial limits of wingless transcription in the Drosophila embryo. Nature366, 560–562 (1993). CASPubMed Google Scholar
Cadigan, K. M., Grossniklaus, U. & Gehring, W. J. Localized expression of sloppy paired protein maintains the polarity of Drosophila parasegments. Genes Dev.8, 899–913 (1994). CASPubMed Google Scholar
Buescher, M. et al. Drosophila T box proteins break the symmetry of hedgehog-dependent activation of wingless. Curr. Biol.14, 1694–1702 (2004). CASPubMed Google Scholar
Kiecker, C. & Lumsden, A. Compartments and their boundaries in vertebrate brain development. Nature Rev. Neurosci.6, 553–564 (2005). CAS Google Scholar
Kiecker, C. & Lumsden, A. Hedgehog signaling from the ZLI regulates diencephalic regional identity. Nature Neurosci.7, 1242–1249 (2004). This paper provides evidence that regionalization in the diencephalon is regulated by the differential competence of thalamic and prethalamic primordia in responding to SHH signalling, and that this competence is regulated by the transcription factor IRX3. CASPubMed Google Scholar
Kobayashi, D. et al. Early subdivisions in the neural plate define distinct competence for inductive signals. Development129, 83–93 (2002). CASPubMed Google Scholar
Green, J. B. & Smith, J. C. Graded changes in dose of a Xenopus activin A homologue elicit stepwise transitions in embryonic cell fate. Nature347, 391–394 (1990). CASPubMed Google Scholar
Wilson, P. A., Lagna, G., Suzuki, A. & Hemmati-Brivanlou, A. Concentration-dependent patterning of the Xenopus ectoderm by BMP4 and its signal transducer Smad1. Development124, 3177–3184 (1997). CASPubMed Google Scholar
McDowell, N., Zorn, A. M., Crease, D. J. & Gurdon, J. B. Activin has direct long-range signalling activity and can form a concentration gradient by diffusion. Curr Biol.7, 671–681 (1997). CASPubMed Google Scholar
Chen, Y. & Schier, A. F. The zebrafish Nodal signal Squint functions as a morphogen. Nature411, 607–610 (2001). CASPubMed Google Scholar
Kiecker, C. & Niehrs, C. A morphogen gradient of Wnt/beta-catenin signalling regulates anteroposterior neural patterning in Xenopus. Development128, 4189–4201 (2001). CASPubMed Google Scholar
Smith, J. C. & Gurdon, J. B. Many ways to make a gradient. Bioessays26, 705–706 (2004). CASPubMed Google Scholar
Scholpp, S. & Brand, M. Endocytosis controls spreading and effective signaling range of Fgf8 protein. Curr. Biol.14, 1834–1841 (2004). CASPubMed Google Scholar
Golembo, M., Schweitzer, R., Freeman, M. & Shilo, B. Z. Argos transcription is induced by the Drosophila EGF receptor pathway to form an inhibitory feedback loop. Development122, 223–230 (1996). CASPubMed Google Scholar
Casci, T., Vinos, J. & Freeman, M. Sprouty, an intracellular inhibitor of Ras signaling. Cell96, 655–665 (1999). CASPubMed Google Scholar
Minowada, G. et al. Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development126, 4465–4467 (1999). CASPubMed Google Scholar
Furthauer, M., Reifers, F., Brand, M., Thisse, B. & Thisse C. sprouty4 acts in vivo as a feedback-induced antagonist of FGF signaling in zebrafish. Development128, 2175–2186 (2001). CASPubMed Google Scholar
Zeng, W. et al. naked cuticle encodes an inducible antagonist of Wnt signalling. Nature403, 789–795 (2000). CASPubMed Google Scholar
Yamashita, Y. M., Jones, D. L. & Fuller, M. T. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science301, 1547–1550 (2003). CASPubMed Google Scholar
Liem, K. F. Jr, Tremml, G. & Jessell, T. M. A role for the roof plate and its resident TGFβ-related proteins in neuronal patterning in the dorsal spinal cord. Cell91, 127–138 (1997). CASPubMed Google Scholar
Song, M. R. & Ghosh, A. FGF2-induced chromatin remodeling regulates CNTF-mediated gene expression and astrocyte differentiation. Nature Neurosci.7, 229–235 (2004). PubMed Google Scholar
Lei, Q. et al. Wnt signalling inhibitors regulate the transcriptional response to morphogenetic Shh–Gli signalling in the neural tube. Dev. Cell11, 325–337 (2006). CASPubMed Google Scholar
Megason, S. G. & McMahon, A. P. A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. Development129, 2087–2098 (2002). CASPubMed Google Scholar
Kent, D., Bush, E. W. & Hooper, J. E. Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus. Development133, 2001–2010 (2006). CASPubMed Google Scholar
Zhang, Q. et al. A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor. Dev. Cell10, 719–729 (2006). CASPubMed Google Scholar