Extracellular modulation of the hedgehog, Wnt and TGF-β signalling pathways during embryonic development

Current Opinion in Genetics and Development

Volumn 9, Issue 4, 1999, Pages 427-433

  Capdevila, Javier ^a   Belmonte, Juan Carlos Izpisúa ^a  

^a SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

SECRETORY PROTEIN; TRANSFORMING GROWTH FACTOR BETA;

DEVELOPMENTAL GENETICS; EMBRYO DEVELOPMENT; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

ERINACEIDAE;

EID: 0033523291     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(99)80065-3     Document Type: Article

References (91)

1. Lawrence PA, Struhl G: Morphogens, compartments, and pattern: Lessons from Drosophila? Cell 1996, 85:951-961.
2. Ingham PW: Transducing Hedgehog: The story so far. EMBO J 1998, 17:3505-3511.
3. Johnson RL, Scott MP: New players and puzzles in the Hedgehog signaling pathway. Curr Opin Genet Dev 1998, 8:450-456.
4. Wodarz A, Nusse R: Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 1998, 14:59-88.
5. Brown JD, Moon RT: Wnt signaling: Why is everything so negative? Curr Opin Cell Biol 1998, 10:182-187.
6. Dierick H, Bejsovec A: Cellular mechanisms of wingless/Wnt signal transduction. Curr Top Dev Biol 1999, 43:153-190.
7. Cho KW, Blitz IL: BMPs, Smads and metalloproteases: Extracellular and intracellular modes of negative regulation. Curr Opin Genet Dev 1998, 8:443-449.
8. Massagué J: TGF-beta signal transduction. Annu Rev Biochem 1998, 67:753-791.
9. Padgett RW, Das P, Krishna S: TGF-beta signaling, Smads, and tumor suppressors. Bioessays 1998, 20:382-390.
10. Alcedo J, Ayzenzon M, Von Ohlen T, Noll M, Hooper JE: The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell 1996, 86:221-232.
11. van den Heuvel M, Ingham PW: Smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. Nature 1996, 382:547-551.
12. Hooper JE, Scott MP: The Drosophila patched gene encodes a putative membrane protein required for segmental patterning. Cell 1989, 59:751-765.
13. Nakano Y, Guerrero I, Hidalgo A, Taylor A, Whittle JR, Ingham PW: A protein with several possible membrane-spanning domains encoded by the Drosophila segment polarity gene patched. Nature 1989, 341:508-513.
14. Marigo V, Davey RA, Zuo Y, Cunningham JM, Tabin CJ: Biochemical evidence that patched is the Hedgehog receptor. Nature 1996, 384:176-179.
15. Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, Scott MP, Pennica D, Goddard A, Phillips H et al.: The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 1996, 384:129-134.
16. Chen Y, Struhl G: In vivo evidence that patched and smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex. Development 1998, 125:4943-4948. Using a probable null allele of the Smo gene, identified in Drosophila, the authors demonstrate that Ptc alone can bind Hh without any help from Smo, which would act as the transducing component of the receptor complex. A model is proposed whereby the binding of Hh to Ptc induces a oonformational change in the latter that results in the release of Smo activity.
17. Chen Y, Struhl G: Dual roles for patched in sequestering and transducing Hedgehog. Cell 1996, 87:553-563.
18. Bellaiche Y, The I, Perrimon N: Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 1999, 394:85-88. The single-span type II transmembrane protein Ttv mediates diffusion of Hh protein across responding cells in the Drosophila wing. The ttv gene is homologous to EXT-1 and EXT-2, genes associated with multiple exostoses (benign bone tumours) in humans. EXT mutations might cause bone alterations by interfering with the diffusion of Indian hedgehog, a Hh protein that acts as a key regulator of bone development.
19. Lin X, Gan L, Klein WH, Wells D: Expression and functional analysis of mouse EXT1, a homolog of the human multiple exostoses type 1 gene. Biochem Biophys Res Commun 1998, 248:738-743.
20. McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP, Tufaro F: The putative tumor suppressor EXT1 alters the expression of cell surface heparan sulfate. Nat Genet 1998, 19:158-161. The EXT1 protein is an endoplasmic-reticulum-resident type II transmembrane glycoprotein involved in the synthesis and display of cell surface heparan sulfate glycosaminoglycans. This provides a possible explanation for the defects in Hh diffusion observed in EXT (or ttv) mutants, as GAGs are known to be involved in the reception of signalling proteins.
21. Chuang PT, McMahon AP: Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999, 397:617-621. Identification of Hip (Hedgehog-interacting protein), a membrane glycoprotein that binds to the three mammalian Hh proteins and attenuates their activities. Hip is also a transcriptional target of Hh, so it follows that Hh proteins modulate their own activities through the establishment of a negative regulatory feedback that involves an inhibitory glycoprotein.
22. Porter JA, Young KE, Beachy PA: Cholesterol modification of hedgehog signaling proteins in animal development. Science 1996, 274:255-259.
23. Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K et al.: Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem 1998, 273:14037-14045. Besides the cholesterol attached to the carboxyl terminus of its amino-terminal fragment, the human Hh protein has a second lipid tether: a palmitoyl group attached to its amino terminus, specifically on the α-amino group of Cys-24. The authors demonstrate that in a cell-based assay the lipid-tethered forms of human Hh are much stronger than the unmodified forms.
24. Rietveld A, Neutz S, Simons K, Eaton S: Association of sterol- and glycosylphosphatidylinositol-linked proteins with Drosophila raft lipid microdomains. J Biol Chem 1999, 274:12049-12054. The authors demonstrate here that sterol-linked Hh amino-terminal fragment associates specifically with lipid rafts. These are lipid microdomains present in cell membranes that have been proposed to act as platforms for the localized concentration, activation or diffusion of signalling proteins.
25. Simons K, Ikonen E: Functional rafts in cell membranes. Nature 1997, 387:569-572.
26. Brown DA, London E: Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 1998, 14:111-136.
27. Nusse R, Varmus HE: Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982, 31:99-109.
28. The Wnt Gene Homepage on the World Wide Web at URL: http://www.stanford.edu/~rnusse/wntwindow.html Roel Nusse's Wnt gene homepage, which includes a regularly updated list of all the members of the Wnt gene family.
29. Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, Andrew D, Nathans J, Nusse R: A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 1996, 382:225-230.
30. Zhang J, Carthew RW: Interactions between Wingless and DFz2 during Drosophila wing development Development 1998, 125:3075-3085. A demonstration that Dfz2 actually functions in the Wg pathway during Drosophila development. The authors show that overexpression of DFz2 in the wing actually enhances Wg-dependent signaling and that overexpression of a truncated form of DFz2 acts in a dominant-negative manner to block Wg signaling.
31. Cadigan KM, Fish MP, Rulifson EJ, Nusse R: Wingless repression of Drosophila frizzled 2 expression shapes the Wingless morphogen gradient in the wing. Cell 1998, 93:767-777. In the Drosophila wing imaginal disk, Wg shapes its own gradient by controlling the expression of a Wg receptor (Dfz2) that plays an important role by protecting Wg from degradation. The authors demonstrate that high levels of DFz2 stabilize Wg, allowing it to reach cells far from its site of synthesis in the dorso-ventral boundary of the wing. Thus, DFz2 is a receptor that broadens the range of action of its ligand.
32. Leyns L, Bouwmeester T, Kim SH, Piccolo S, De Robertis EM: Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann organizer. Cell 1997, 88:747-756.
33. Mayr T, Deutsch U, Kuhl M, Drexler HC, Lottspeich F, Deutzmann R, Wedlich D, Risau W: Fritz: A secreted frizzled-related protein that inhibits Wnt activity. Mech Dev 1997, 63:109-125.
34. Finch PW, He X, Kelley MJ, Uren A, Schaudies RP, Popescu NC, Rudikoff S, Aaronson SA, Varmus HE, Rubin JS: Purification and molecular cloning of a secreted, Frizzled-related antagonist of wnt action. Proc Natl Acad Sci USA 1997, 94:6770-6775.
35. Salic AN, Kroll KL, Evans LM, Kirschner MW: Sizzled: A secreted wnt8 antagonist expressed in the ventral marginal zone of Xenopus embryos. Development 1997, 124:4739-4748.
36. Lin K, Wang S, Julius MA, Kitajewski J, Moos M Jr, Luyten FP: The cysteine-rich frizzled domain of Frzb-1 is required and sufficient for modulation of Wnt signaling. Proc Natl Acad Sci USA 1997, 94:11196-11200.
37. Wang S, Krinks M, Lin K, Luyten FP, Moos M Jr: Frzb, a secreted protein expressed in the Spemann organizer, binds and inhibits Wnt-8. Cell 1997, 88:757-766.
38. Rattner A, Hsieh JC, Smallwood PM, Gilbert DJ, Copeland NG, Jenkins NA, Nathans J: A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. Proc Natl Acad Sci USA 1997, 94:2859-2863.
39. Melkonyan HS, Chang WC, Shapiro JP, Mahadevappa M, Fitzpatrick PA, Kiefer MC, Tomei LD, Umansky SR: SARPs: A family of secreted apoptosis-related proteins. Proc Natl Acad Sci USA 1997, 94:13636-13641.
40. Leimeister C, Bach A, Gessler M: Developmental expression patterns of mouse sFRP genes encoding members of the secreted frizzled related protein family. Mech Dev 1998, 75:29-42. This paper illustrates the complexity in the spatial and temporal regulation of the transcription of several extracellular inhibitors of Wnts in the mouse embryo. Different mouse sFRPs are specifically expressed in structures such as the embryonic metanephros, brain, eye, salivary gland, teeth, and small intestine. This underscores the importance of taking into account the likely presence of antagonists when studying the role of Wnt factors in all these embryonic structures.
41. Wang S, Krinks M, Moos M Jr: Frzb-1, an antagonist of Wnt-1 and Wnt-8, does not block signaling by Wnts -3A, -5A, or -11. Biochem Biophys Res Commun 1997, 236:502-504.
42. Lescher B, Haenig B, Kispert A: sFRP-2 is a target of the Wnt-4 signaling pathway in the developing metanephric kidney. Dev Dyn 1998, 213:440-451.
43. Hoppler S, Brown JD, Moon RT: Expression of a dominant-negative Wnt blocks induction of MyoD in Xenopus embryos. Genes Dev 1996, 10:2805-2817.
44. Torres MA, Yang-Snyder JA, Purcell SM, DeMarais AA, McGrew LL, Moon RT: Activities of the Wnt-1 class of secreted signaling factors are antagonized by the Wnt-5A class and by a dominant negative cadherin in early Xenopus development. J Cell Biol 1996, 133:1123-1137.
45. Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C: Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 1998, 391:357-362. Identification of a novel secreted factor that antagonizes Wnt signalling and is sufficient and necessary to cause head induction in Xenopus. Experiments of co-expression with several known components of the Wnt pathway demonstrate that Dkk-1 most likely blocks the pathway by interacting directly with Wnt proteins or Wnt receptors.
46. Aravind L, Koonin EV: A colipase fold in the carboxy-terminal domain of the Wnt antagonists - the Dickkopfs. Curr Biol 1998, 8:R477-R478.
47. Hsieh J-C, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Harryman Samos C, Nusse R, Dawid IB, Nathans J. A new secreted protein that binds to Wnt proteins and inhibits their activites. Nature 1999, 398:431-436. Identification of the novel secreted factor Wnt-inhibitory factor-1 as an extracellular inhibitor of Wnts involved in the development of paraxial mesoderm in Xenopus and zebrafish. Specifically, the paper shows that overexpression of this factor in Xenopus affects the generation of trunk mesoderm segments, indicating its requirement during somitogenesis.
48. Binari RC, Staveley BE, Johnson WA, Godavarti R, Sasisekharan R, Manoukian AS: Genetic evidence that heparin-like glycosaminoglycans are involved in wingless signaling. Development 1997, 124:2623-2632.
49. Hacker U, Lin X, Perrimon N: The Drosophila sugarless gene modulates Wingless signaling and encodes an enzyme involved in polysaccharide biosynthesis. Development 1997, 124:3565-3573.
50. Haerry TE, Heslip TR, Marsh JL, O'Connor MB: Defects in glucuronate biosynthesis disrupt Wingless signaling in Drosophila. Development 1997, 124:3055-3064.
51. Dierick HA, Bejsovec A: Functional analysis of Wingless reveals a link between intercellular ligand transport and dorsal-cell-specific signaling. Development 1998, 125:4729-4738.
52. Hogan BL: Bone morphogenetic proteins in development. Curr Opin Genet Dev 1996, 6:432-438.
53. Lecuit T, Cohen SM: Dpp receptor levels contribute to shaping the Dpp morphogen gradient in the Drosophila wing imaginai disc. Development 1998, 125:4901-4907. High levels of expression of the Dpp receptor Tkv play a double role by sensitizing cells to low levels of Dpp and by limiting the movement of Dpp. Tkv expression is negatively regulated by Dpp, so this is another example of a signalling molecule controlling its own activity through the regulation of its receptor levels.
54. Haerry TE, Khalsa O, O'Connor MB, Wharton KA: Synergistic signaling by two BMP ligands through the SAX and TKV receptors controls wing growth and patterning in Drosophila. Development 1998, 125:3977-3987. In the Drosophila wing, the Dpp receptor Tkv limits the movement of Dpp such that the levels of expression of Tkv are kept relatively low to allow lowrange diffusion of Dpp. The authors show that a second TGF-β ligand, GBB (Glass Bottom Boat), interacts with a receptor called Sax and synergistically enhances Tkv signalling. This paper elegantly illustrates a case of synergistic signalling by multiple TGF-β ligands and receptors with relevance to developmental mechanisms.
55. Nguyen M, Park S, Marqués G, Arora K: Interpretation of a BMP activity gradient in Drosophila embryos depends on synergistic signaling by two type I receptors, SAX and TKV. Cell 1998, 95:495-506. The interaction of Dpp with its receptor, Tkv, is required for the correct specification of dorsal embryonic cell fates in Drosophila. This paper shows that a second TG F-β, Screw, interacts with the Sax receptor to potentiate Dpp signalling. The extracellular inhibitor Sog is able to bind Screw, thus interfering with its potentiating activity. These results expand the notion of the existence of synergistic signalling by multiple TGF-β ligands and receptors to the dorso-ventral determination in the early Drosophila embryo.
56. Smith WC: TGF beta inhibitors. New and unexpected requirements in vertebrate development. Trends Genet 1999, 15:3-5.
57. Iemura S, Yamamoto TS, Takagi C, Uchiyama H, Natsume T, Shimasaki S, Sugino H, Ueno N: Direct binding of follistatin to a complex of bone morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc Natl Acad Sci USA 1998, 95:9337-9342.
58. Sasai Y, Lu B, Steinbeisser H, Geissert D, Gont LK, De Robertis EM: Xenopus chordin: A novel dorsalizing factor activated by organizer-specific homeobox genes. Cell 1994, 79:779-790.
59. Sasai Y, Lu B, Steinbeisser H, De Robertis EM: Regulation of neural induction by the Chd and Bmp-4 antagonistic patterning signals in Xenopus. Nature 1995, 376:333-336.
60. Smith WC, Harland RM: Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell 1992, 70:829-840.
61. Lamb TM, Knecht AK, Smith WC, Stachel SE, Economides AN, Stahl N, Yancopolous GD, Harland RM: Neural induction by the secreted polypeptide noggin. Science 1993, 262:713-718.
62. Smith WC, Knecht AK, Wu M, Harland RM: Secreted noggin protein mimics the Spemann organizer in dorsalizing Xenopus mesoderm. Nature 1993, 361:547-549.
63. Piccolo S, Sasai Y, Lu B, De Robertis EM: Dorsoventral patterning in Xenopus: Inhibition of ventral signals by direct binding of chordin to BMP-4. Cell 1996, 86:589-598.
64. Zimmerman LB, De Jesus-Escobar JM, Harland RM: The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 1996, 86:599-606.
65. Thomsen GH: Antagonism within and around the organizer: BMP inhibitors in vertebrate body patterning. Trends Genet 1997, 13:209-211.
66. Hsu DR, Economides AN, Wang X, Eimon PM, Harland RM: The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol Cell 1998, 1:673-683. Gremlin, Cerberus and Dan constitute a family of secreted factors that bind BMPs and have no sequence similarity to Noggin and Chordin. The paper also shows that Cerberus alone blocks signaling by Activin-like and Nodallike members of the TGF-β superfamily, which indicates that members of the Gremlin/Cerberus/Dan family selectively antagonize the activities of different subsets of TGF-β ligands.
67. Bouwmeester T, Kim S, Sasai Y, Lu B, De Robertis EM: Cerberus is a head inducing secreted factor expressed in the anterior endoderm of Spemann's organizer. Nature 1996, 382:595-601.
68. Piccolo S, Agius E, Leyns L, Bhattacharyya S, Grunz H, Bouwmeester T, De Robertis EM: The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 1999, 397:707-710. This is the first description of a secreted antagonist that binds to members of several families of signalling molecules (Nodal, BMP and Wnt) via independent sites. Antagonism of BMP, Wnt and Nodal signalling by Cerberus seems to be required for inhibition of trunk development (and head induction) in rostral regions of the Xenopus embryo.
69. Nakamura Y, Ozaki T, Nakagawara A, Sakiyama S: A product of DAN, a novel candidate tumour suppressor gene, is secreted into culture medium and suppresses DNA synthesis. Eur J Cancer 1997, 33:1986-1990.
70. Stanley E, Biben C, Kotecha S, Fabri L, Tajbakhsh S, Wang CC, Hatzistavrou T, Roberts B, Drinkwater C, Lah M et al.: DAN is a secreted glycoprotein related to Xenopus cerberus. Mech Dev 1998, 77:173-184.
71. Belo JA, Bouwmeester T, Leyns L, Kertesz N, Gallo M, Follettie M, De Robertis EM: Cerberus-like is a secreted factor with neutralizing activity expressed in the anterior primitive endoderm of the mouse gastrula. Mech Dev 1997, 68:45-57.
72. Biben C, Stanley E, Fabri L, Kotecha S, Rhinn M, Drinkwater C, Lah M, Wang CC, Nash A, Hilton D et al.: Murine cerberus homologue mCer-1: A candidate anterior patterning molecule. Dev Biol 1998, 194:135-151.
73. Minabe-Saegusa C, Saegusa H, Tsukahara M, Noguchi S: Sequence and expression of a novel mouse gene PRDC (protein related to DAN and cerberus) identified by a gene trap approach. Dev Growth Differ 1998, 40:343-353.
74. Pearce JJH, Penny G, Rossant J: A mouse Cerberus/Dan-related Gene Family. Dev Biol 1999, 209:98-110.
75. Shawlot W, Deng JM, Behringer RR: Expression of the mouse cerberus-related gene, Cerr1, suggests a role in anterior neural induction and somitogenesis. Proc Natl Acad Sci USA 1998, 95:6198-6203.
76. Gazzerro E, Gangji V, Canalis E: Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts. J Clin Invest 1998, 102:2106-2114.
77. Amthor H, Christ B, Patel K: A molecular mechanism enabling continuous embryonic muscle growth - a balance between proliferation and differentiation. Development 1999, 126:1041-1053.
78. Constam DB, Robertson EJ: Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases. J Cell Biol 1999, 144:139-149. Mature BMPs result from endoproteolytic cleavage of inactive precursors. The authors show that the stability of the mature forms of several BMPs is highly dependent on the identity of the residues adjacent to the precursor cleavage site.
79. Suzuki A, Kaneko E, Maeda J, Ueno N: Mesoderm induction by BMP-4 and -7 heterodimers. Biochem Biophys Res Commun 1997, 232:153-156.
80. Nishimatsu S, Thomsen GH: Ventral mesoderm induction and patterning by bone morphogenetic protein heterodimers in Xenopus embryos. Mech Dev 1998, 74:75-88.
81. Cui Y, Jean F, Thomas G, Christian JL: BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development. EMBO J 1998, 17:4735-4743. The authors here provide evidence that serine endoproteases proteolytically activate BMP-4 during vertebrate embryogenesis, by cleaving its inactive precursor following a specific amino acid motif. Inhibitors of furin are able to phenocopy the effect of blocking endogenous BMP activity in Xenopus embryos.
82. Jackson SM, Nakato H, Sugiura M, Jannuzi A, Oakes R, Kaluza V, Golden C, Selleck SB: Dally, a Drosophila glypican, controls cellular responses to the TGF beta-related morphogen, Dpp. Development 1997, 124:4113-4120.
83. Barbara NP, Wrana JL, Letarte M: Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem 1999, 274:584-594.
84. López-Casillas F, Payne HM, Andres JL, Massagué J: Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: Mapping of ligand binding and GAG attachment sites. J Cell Biol 1994, 124:557-568.
85. Glinka A, Wu W, Onichtchouk D, Blumenstock C, Niehrs C: Head induction by simultaneous repression of Bmp and Wnt signalling in Xenopus. Nature 1997, 389:517-519.
86. Ashe HL, Levine M: Local inhibition and long-range enhancement of Dpp signal transduction by Sog. Nature 1999, 398:427-431. This is the first description of a BMP antagonist exerting completely opposite effects on a BMP at short versus long range. In the Drosophila embryo, Sog antagonizes Dpp signalling at short range but it facilitates Dpp signalling at long range by an unknown mechanism. This result sheds light on the (formerly) puzzling observation that in sog mutant embryos, the Dpp-dependent extra-embryonic tissue called amnioserosa is absent.
87. Blader P, Rastegar S, Fischer N, Strahle U: Cleavage of the Bmp-4 antagonist chordin by zebrafish tolloid. Science 1997, 278:1937-1940.
88. Marqués G, Musacchio M, Shimell MJ, Wunnenberg-Stapleton K, Cho KW, O'Connor MB: Production of a DPP activity gradient in the early Drosophila embryo through the opposing actions of the SOG and TLD proteins. Cell 1997, 91:417-426.
89. Piccolo S, Agius E, Lu B, Goodman S, Dale L, De Robertis EM: Cleavage of Chordin by Xolloid metalloprotease suggests a role for proteolytic processing in the regulation of Spemann organizer activity. Cell 1997, 91:407-416.
90. Bier E: A unity of opposites. Nature 1999 398:375-376.
91. Perrimon N, McMahon AP: Negative feedback mechanisms and their roles during pattern formation. Cell 1999, 97:13-16.