Nipbl and Mediator Cooperatively Regulate Gene Expression to Control Limb Development

PLoS Genetics

Volumn 10, Issue 9, 2014, Pages

  Muto, Akihiko ^a,b   Ikeda, Shingo ^b   Lopez Burks, Martha E ^a   Kikuchi, Yutaka ^b   Calof, Anne L ^b,c   Lander, Arthur D ^a   Schilling, Thomas F ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b HIROSHIMA UNIVERSITY   (Japan)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FIBROBLAST GROWTH FACTOR; MED12 PROTEIN; NIPBL PROTEIN; REGULATOR PROTEIN; TRANSCRIPTOME; UNCLASSIFIED DRUG; CHROMATIN; NIPBL PROTEIN, MOUSE; NIPBL PROTEIN, ZEBRAFISH; PROTEIN BINDING; TRANSCRIPTION FACTOR; ZEBRAFISH PROTEIN;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DEVELOPMENTAL GENE; DISEASE ACTIVITY; EMBRYO; FGF GENE; GENE CLUSTER; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENE FUNCTION; GENE IDENTIFICATION; GENE LOCATION; HAND2 GENE; HOX GENE; LIMB DEVELOPMENT; MESENCHYME; MOLECULAR DYNAMICS; MOLECULAR PATHOLOGY; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; PROTEIN DETERMINATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; RNA SEQUENCE; SEQUENCE ANALYSIS; SHHA GENE; SIGNAL TRANSDUCTION; ZEBRA FISH; ANIMAL; CHROMATIN; DEFICIENCY; EMBRYOLOGY; GENETICS; HAPLOINSUFFICIENCY; HOMEOBOX; KNOCKOUT MOUSE; LIMB; METABOLISM; ORGANOGENESIS; PHENOTYPE; TRANSGENIC ANIMAL;

ANIMALS; ANIMALS, GENETICALLY MODIFIED; CHROMATIN; EXTREMITIES; GENE EXPRESSION REGULATION, DEVELOPMENTAL; GENES, HOMEOBOX; HAPLOINSUFFICIENCY; MICE; MICE, KNOCKOUT; ORGANOGENESIS; PHENOTYPE; PROTEIN BINDING; TRANSCRIPTION FACTORS; ZEBRAFISH; ZEBRAFISH PROTEINS;

EID: 84907584621     PISSN: 15537390     EISSN: 15537404     Source Type: Journal    
DOI: 10.1371/journal.pgen.1004671     Document Type: Article

References (110)

1. Peters JM, Tedeschi A, Schmitz J, (2008) The cohesin complex and its roles in chromosome biology. Genes Dev 22: 3089–3114.
2. Remeseiro S, Losada A, (2013) Cohesin, a chromatin engagement ring. Curr Opin Cell Biol 25: 63–71.
3. Kawauchi S, Calof AL, Santos R, Lopez-Burks ME, Young CM, et al. (2009) Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl +/2 Mouse, a Model of Cornelia de Lange Syndrome. PLoS Genet 5: e1000650.
4. Liu J, Zhang Z, Bando M, Itoh T, Deardorff MA, et al. (2009) Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human Cells. PLoS Biol 7: e1000119.
5. Rollins RA, Korom M, Aulner N, Martens A, Dorsett D, (2004) Drosophila Nipped-B Protein Supports Sister Chromatid Cohesion and Opposes the Stromalin/Scc3 Cohesion Factor To Facilitate Long-Range Activation of the cut Gene. Mol Cell Biol 24: 3100–3111.
6. Dorsett D, Eissenberg JC, Misulovin Z, Martens A, Redding B, et al. (2005) Effects of sister chromatid cohesion proteins on cut gene expression during wing development in Drosophila. Development 132: 4743–4753.
7. Wendt KS, Yoshida K, Itoh T, Bando M, Koch B, et al. (2008) Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature 451: 796–801.
8. Parelho V, Hadjur S, Spivakov M, Leleu M, Sauer S, et al. (2008) Cohesins Functionally Associate with CTCF on Mammalian Chromosome Arms. Cell 132: 422–433.
9. Rhodes JM, Bentley FK, Print CG, Dorsett D, Misulovin Z, et al. (2010) Positive regulation of c-Myc by cohesin is direct, and evolutionarily conserved. Dev Biol 344: 637–649.
10. Dorsett D, (2011) Cohesin: genomic insights into controlling gene transcription and development. Curr Opin Genet Dev 21: 199–206.
11. Muto A, Calof AL, Lander AD, Schilling TF, (2011) Multifactorial Origins of Heart and Gut Defects in nipbl-Deficient Zebrafish, a Model of Cornelia de Lange Syndrome. PLoS Biol 9: e1001181.
12. Dorsett D, Strom L, (2012) The ancient and evolving roles of cohesin in gene expression and DNA repair. Curr Biol 22: R240–250.
13. Chien R, Zeng W, Kawauchi S, Bender MA, Santos R, et al. (2011) Cohesin mediates chromatin interactions that regulate mammalian beta-globin expression. J Biol Chem 286: 17870–17878.
14. Amano T, Sagai T, Tanabe H, Mizushina Y, Nakazawa H, et al. (2009) Chromosomal dynamics at the Shh locus: limb bud-specific differential regulation of competence and active transcription. Dev Cell 16: 47–57.
15. Montavon T, Soshnikova N, Mascrez B, Joye E, Thevenet L, et al. (2011) A regulatory archipelago controls Hox genes transcription in digits. Cell 147: 1132–1145.
16. Ferrai C, Pombo A, (2009) 3D chromatin regulation of Sonic hedgehog in the limb buds. Dev Cell 16: 9–11.
17. Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, et al. (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467: 430–435.
18. Borggrefe T, Yue X, (2011) Interactions between subunits of the Mediator complex with gene-specific transcription factors. Semin Cell Dev Biol 22: 759–768.
19. Ries D, Meisterernst M, (2011) Control of gene transcription by Mediator in chromatin. Semin Cell Dev Biol 22: 735–740.
20. Knuesel MT, Meyer KD, Bernecky C, Taatjes DJ, (2009) The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function. Genes Dev 23: 439–451.
21. Hengartner CJ, Myer VE, Liao SM, Wilson CJ, Koh SS, et al. (1998) Temporal regulation of RNA polymerase II by Srb10 and Kin28 cyclin-dependent kinases. Mol Cell 2: 43–53.
22. Akoulitchev S, Chuikov S, Reinberg D, (2000) TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407: 102–106.
23. Furumoto T, Tanaka A, Ito M, Malik S, Hirose Y, et al. (2007) A kinase subunit of the human mediator complex, CDK8, positively regulates transcriptional activation. Genes Cells 12: 119–132.
24. Belakavadi M, Fondell JD, (2010) Cyclin-dependent kinase 8 positively cooperates with Mediator to promote thyroid hormone receptor-dependent transcriptional activation. Mol Cell Biol 30: 2437–2448.
25. Ireland M, Donnai D, Burn J, (1993) Brachmann-de Lange Syndrome. Delineation of the Clinical Phenotype. Am J Med Genet 47: 959–964.
26. Jackson L, Kline AD, Barr MA, Koch S, (1993) de Lange Syndrome: A Clinical Review of 310 Individuals. Am J Med Genet 47: 940–946.
27. Kline AD, Krantz ID, Sommer A, Kliewer M, Jackson LG, et al. (2007) Cornelia de Lange Syndrome: Clinical Review, Diagnostic and Scoring Systems, and Anticipatory Guidance. Am J Med Genet A 143A: 1287–1296.
28. Liu J, Krantz ID, (2008) Cohesin and Human Disease. Annu Rev Genomics Hum Genet 9: 303–320.
29. Strachan T, (2005) Cornelia de Lange Syndrome and the link between chromosomal function, DNA repair and developmental gene regulation. Curr Opin Genet Dev 15: 258–264.
30. Bose T, Gerton JL, (2010) Cohesinopathies, gene expression, and chromatin organization. J Cell Biol 189: 201–210.
31. Tonkin ET, Wang T-J, Lisgo S, Bamshad MJ, Strachan T, (2004) NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet 36: 636–641.
32. Krantz ID, McCallum J, DeScipio C, Kaur M, Gillis LA, et al. (2004) Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet 36: 631–635.
33. Musio A, Selicorni A, Focarelli ML, Gervasini C, Milani D, et al. (2006) X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet 38: 528–530.
34. Deardorff MA, Kaur M, Yaeger D, Rampuria A, Korolev S, et al. (2007) Mutations in Cohesin Complex Members SMC3 and SMC1A Cause a Mild Variant of Cornelia de Lange Syndrome with Predominant Mental Retardation. Am J Hum Genet 80: 485–494.
35. Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T, et al. (2012) HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489: 313–317.
36. Dorsett D, Krantz ID, (2009) On the Molecular Etiology of Cornelia de Lange Syndrome. Ann N Y Acad Sci 1151: 21–37.
37. Rau MJ, Fischer S, Neumann CJ, (2006) Zebrafish Trap230/Med12 is required as a coactivator for Sox9-dependent neural crest, cartilage and ear development. Dev Biol 296: 83–93.
38. Mercader N, (2007) Early steps of paired fin development in zebrafish compared with tetrapod limb development. Dev Growth Differ 49: 421–437.
39. Abbasi AA, (2011) Evolution of vertebrate appendicular structures: Insight from genetic and palaeontological data. Dev Dyn 240: 1005–1016.
40. Benazet JD, Zeller R, (2009) Vertebrate limb development: moving from classical morphogen gradients to an integrated 4-dimensional patterning system. Cold Spring Harb Perspect Biol 1: a001339.
41. Mari-Beffa M, Murciano C, (2010) Dermoskeleton morphogenesis in zebrafish fins. Dev Dyn 239: 2779–2794.
42. Gibert Y, Gajewski A, Meyer A, Begemann G, (2006) Induction and prepatterning of the zebrafish pectoral fin bud requires axial retinoic acid signaling. Development 133: 2649–2659.
43. Mic FA, Sirbu IO, Duester G, (2004) Retinoic acid synthesis controlled by Raldh2 is required early for limb bud initiation and then later as a proximodistal signal during apical ectodermal ridge formation. J Biol Chem 279: 26698–26706.
44. Niederreither K, Vermot J, Schuhbaur B, Chambon P, Dolle P, (2002) Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Development 129: 3563–3574.
45. Prykhozhij SV, Neumann CJ, (2008) Distinct roles of Shh and Fgf signaling in regulating cell proliferation during zebrafish pectoral fin development. BMC Dev Biol 8: 91.
46. Grandel H, Draper BW, Schulte-Merker S, (2000) dackel acts in the ectoderm of the zebrafish pectoral fin bud to maintain AER signaling. Development 127: 4169–4178.
47. Grandel H, Schulte-Merker S, (1998) The development of the paired fins in the zebrafish (Danio rerio). Mech Dev 79: 99–120.
48. Yano T, Abe G, Yokoyama H, Kawakami K, Tamura K, (2012) Mechanism of pectoral fin outgrowth in zebrafish development. Development 139: 2916–2925.
49. Fischer S, Draper BW, Neumann CJ, (2003) The zebrafish fgf24 mutant identifies an additional level of Fgf signaling involved in vertebrate forelimb initiation. Development 130: 3515–3524.
50. Nomura R, Kamei E, Hotta Y, Konishi M, Miyake A, et al. (2006) Fgf16 is essential for pectoral fin bud formation in zebrafish. Biochem Biophys Res Commun 347: 340–346.
51. Norton WH, Ledin J, Grandel H, Neumann CJ, (2005) HSPG synthesis by zebrafish Ext2 and Extl3 is required for Fgf10 signalling during limb development. Development 132: 4963–4973.
52. Ohuchi H, Nakagawa T, Yamamoto A, Araga A, Ohata T, et al. (1997) The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor. Development 124: 2235–2244.
53. Camarata T, Snyder D, Schwend T, Klosowiak J, Holtrup B, et al. (2010) Pdlim7 is required for maintenance of the mesenchymal/epidermal Fgf signaling feedback loop during zebrafish pectoral fin development. BMC Dev Biol 10: 104.
54. Hill RE, (2007) How to make a zone of polarizing activity: insights into limb development via the abnormality preaxial polydactyly. Dev Growth Differ 49: 439–448.
55. Neumann CJ, Grandel H, Gaffield W, Schulte-Merker S, Nusslein-Volhard C, (1999) Transient establishment of anteroposterior polarity in the zebrafish pectoral fin bud in the absence of sonic hedgehog activity. Development 126: 4817–4826.
56. Sakamoto K, Onimaru K, Munakata K, Suda N, Tamura M, et al. (2009) Heterochronic shift in Hox-mediated activation of sonic hedgehog leads to morphological changes during fin development. PLoS One 4: e5121.
57. Yelon D, Ticho B, Halpern ME, Ruvinsky I, Ho RK, et al. (2000) The bHLH transcription factor hand2 plays parallel roles in zebrafish heart and pectoral fin development. Development 127: 2573–2582.
58. Galli A, Robay D, Osterwalder M, Bao X, Benazet JD, et al. (2010) Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet 6: e1000901.
59. Buscher D, Bosse B, Heymer J, Ruther U, (1997) Evidence for genetic control of Sonic hedgehog by Gli3 in mouse limb development. Mech Dev 62: 175–182.
60. Tyurina OV, Guner B, Popova E, Feng J, Schier AF, et al. (2005) Zebrafish Gli3 functions as both an activator and a repressor in Hedgehog signaling. Dev Biol 277: 537–556.
61. Mercader N, Fischer S, Neumann CJ, (2006) Prdm1 acts downstream of a sequential RA, Wnt and Fgf signaling cascade during zebrafish forelimb induction. Development 133: 2805–2815.
62. Zakany J, Duboule D, (2007) The role of Hox genes during vertebrate limb development. Curr Opin Genet Dev 17: 359–366.
63. Kmita M, Tarchini B, Zakany J, Logan M, Tabin CJ, et al. (2005) Early developmental arrest of mammalian limbs lacking HoxA/HoxD gene function. Nature 435: 1113–1116.
64. Ahn D, Ho RK, (2008) Tri-phasic expression of posterior Hox genes during development of pectoral fins in zebrafish: implications for the evolution of vertebrate paired appendages. Dev Biol 322: 220–233.
65. Tarchini B, Duboule D, (2006) Control of Hoxd genes' collinearity during early limb development. Dev Cell 10: 93–103.
66. Anderson E, Peluso S, Lettice LA, Hill RE, (2012) Human limb abnormalities caused by disruption of hedgehog signaling. Trends Genet 28: 364–373.
67. Williams TM, Williams ME, Kuick R, Misek D, McDonagh K, et al. (2005) Candidate downstream regulated genes of HOX group 13 transcription factors with and without monomeric DNA binding capability. Dev Biol 279: 462–480.
68. Salsi V, Zappavigna V, (2006) Hoxd13 and Hoxa13 directly control the expression of the EphA7 Ephrin tyrosine kinase receptor in developing limbs. J Biol Chem 281: 1992–1999.
69. Zakany J, Kmita M, Duboule D, (2004) A dual role for Hox genes in limb anterior-posterior asymmetry. Science 304: 1669–1672.
70. Shin CH, Chung WS, Hong SK, Ober EA, Verkade H, et al. (2008) Multiple roles for Med12 in vertebrate endoderm development. Dev Biol 317: 467–479.
71. Horsfield JA, Anagnostou SH, Hu JK-H, Cho KHY, Geisler R, et al. (2007) Cohesin-dependent regulation of Runx genes. Development 134: 2639–2649.
72. Andrey G, Montavon T, Mascrez B, Gonzalez F, Noordermeer D, et al. (2013) A switch between topological domains underlies HoxD genes collinearity in mouse limbs. Science 340: 1234167.
73. Tschopp P, Duboule D, (2011) A genetic approach to the transcriptional regulation of Hox gene clusters. Annu Rev Genet 45: 145–166.
74. Spitz F, (2010) Control of vertebrate Hox clusters by remote and global cis-acting regulatory sequences. Adv Exp Med Biol 689: 63–78.
75. Schneider I, Aneas I, Gehrke AR, Dahn RD, Nobrega MA, et al. (2011) Appendage expression driven by the Hoxd Global Control Region is an ancient gnathostome feature. Proc Natl Acad Sci U S A 108: 12782–12786.
76. Amemiya CT, Alfoldi J, Lee AP, Fan S, Philippe H, et al. (2013) The African coelacanth genome provides insights into tetrapod evolution. Nature 496: 311–316.
77. Woltering JM, Noordermeer D, Leleu M, Duboule D, (2014) Conservation and divergence of regulatory strategies at hox Loci and the origin of tetrapod digits. PLoS Biol 12: e1001773.
78. Mateos-Langerak J, Bohn M, de Leeuw W, Giromus O, Manders EM, et al. (2009) Spatially confined folding of chromatin in the interphase nucleus. Proc Natl Acad Sci U S A 106: 3812–3817.
79. Bohn M, Heermann DW, (2010) Diffusion-driven looping provides a consistent framework for chromatin organization. PLoS One 5: e12218.
80. Noordermeer D, Leleu M, Splinter E, Rougemont J, De Laat W, et al. (2011) The dynamic architecture of Hox gene clusters. Science 334: 222–225.
81. Misulovin Z, Schwartz YB, Li X-Y, Kahn TG, Gause M, et al. (2008) Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome. Chromosoma 117: 89–102.
82. DeMare LE, Leng J, Cotney J, Reilly SK, Yin J, et al. (2013) The genomic landscape of cohesin-associated chromatin interactions. Genome Res 23: 1224–1234.
83. Zuin J, Dixon JR, van der Reijden MI, Ye Z, Kolovos P, et al. (2014) Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci U S A 111: 996–1001.
84. Ong CT, Corces VG, (2011) Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet 12: 283–293.
85. Zuin J, Franke V, van Ijcken WF, van der Sloot A, Krantz ID, et al. (2014) A cohesin-independent role for NIPBL at promoters provides insights in CdLS. PLoS Genet 10: e1004153.
86. Nolen LD, Boyle S, Ansari M, Pritchard E, Bickmore WA, (2013) Regional chromatin decompaction in Cornelia de Lange syndrome associated with NIPBL disruption can be uncoupled from cohesin and CTCF. Hum Mol Genet 22: 4180–4193.
87. Charite J, McFadden DG, Olson EN, (2000) The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development. Development 127: 2461–2470.
88. Xu B, Wellik DM, (2011) Axial Hox9 activity establishes the posterior field in the developing forelimb. Proc Natl Acad Sci U S A 108: 4888–4891.
89. Chambeyron S, Da Silva NR, Lawson KA, Bickmore WA, (2005) Nuclear re-organisation of the Hoxb complex during mouse embryonic development. Development 132: 2215–2223.
90. Kraus P, Fraidenraich D, Loomis CA, (2001) Some distal limb structures develop in mice lacking Sonic hedgehog signaling. Mech Dev 100: 45–58.
91. Chiang C, Litingtung Y, Harris MP, Simandl BK, Li Y, et al. (2001) Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol 236: 421–435.
92. Yan J, Saifi GM, Wierzba TH, Withers M, Bien-Willner GA, et al. (2006) Mutational and Genotype–Phenotype Correlation Analyses in 28 Polish Patients With Cornelia de Lange Syndrome. Am J Med Genet A 140A: 1531–1541.
93. Oliveira J, Dias C, Redeker E, Costa E, Silva J, et al. (2010) Development of NIPBL locus-specific database using LOVD: from novel mutations to further genotype-phenotype correlations in Cornelia de Lange Syndrome. Hum Mutat 31: 1216–1222.
94. Westerfield M (1995) The Zebrafish Book. A Guide for the Laboratory Use of Zebrafish (Danio rerio). Eugene, OR: University of Oregon Press.
95. Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF, (1995) Stages of embryonic development of the zebrafish. Dev Dyn 203: 253–310.
96. Kawauchi S, Takahashi S, Nakajima O, Ogino H, Morita M, et al. (1999) Regulation of lens fiber cell differentiation by transcription factor c-Maf. J Biol Chem 274: 19254–19260.
97. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, et al. (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75: 1417–1430.
98. Shepard JL, Stern HM, Pfaff KL, Amatruda JF, (2004) Analysis of the cell cycle in zebrafish embryos. Methods Cell Biol 76: 109–125.
99. Solovei I, Grasser F, Lanctot C, (2007) FISH on Histological Sections. CSH Protoc 2007: pdb prot4729.
100. Muller S, Neusser M, Kohler D, Cremer M, (2007) Preparation of Complex DNA Probe Sets for 3D FISH with up to Six Different Fluorochromes. CSH Protoc 2007: pdb prot4730.
101. Itou J, Taniguchi N, Oishi I, Kawakami H, Lotz M, et al. (2011) HMGB factors are required for posterior digit development through integrating signaling pathway activities. Dev Dyn 240: 1151–1162.
102. Capellini TD, Di Giacomo G, Salsi V, Brendolan A, Ferretti E, et al. (2006) Pbx1/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and Shh expression. Development 133: 2263–2273.
103. Salsi V, Vigano MA, Cocchiarella F, Mantovani R, Zappavigna V, (2008) Hoxd13 binds in vivo and regulates the expression of genes acting in key pathways for early limb and skeletal patterning. Dev Biol 317: 497–507.
104. Lettice LA, Williamson I, Wiltshire JH, Peluso S, Devenney PS, et al. (2012) Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev Cell 22: 459–467.
105. Liu Z, Lavine KJ, Hung IH, Ornitz DM, (2007) FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev Biol 302: 80–91.
106. Hung IH, Yu K, Lavine KJ, Ornitz DM, (2007) FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol 307: 300–313.
107. Pandur P, Lasche M, Eisenberg LM, Kuhl M, (2002) Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 418: 636–641.
108. Darken RS, Wilson PA, (2001) Axis induction by wnt signaling: Target promoter responsiveness regulates competence. Dev Biol 234: 42–54.
109. Yamamoto S, Nishimura O, Misaki K, Nishita M, Minami Y, et al. (2008) Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev Cell 15: 23–36.
110. Nam JS, Park E, Turcotte TJ, Palencia S, Zhan X, et al. (2007) Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb. Dev Biol 311: 124–135.