Genetic Dissection of Differential Signaling Threshold Requirements for the Wnt/β-Catenin Pathway
Contributions of null and hypomorphic alleles of Apc in mice produce both developmental and pathophysiological phenotypes. To ascribe the resulting genotype-to-phenotype relationship unambiguously to the Wnt/β-catenin pathway, we challenged the allele combinations by genetically restricting intracellular β-catenin expression in the corresponding compound mutant mice. Subsequent evaluation of the extent of resulting Tcf4-reporter activity in mouse embryo fibroblasts enabled genetic measurement of Wnt/β-catenin signaling in the form of an allelic series of mouse mutants. Different permissive Wnt signaling thresholds appear to be required for the embryonic development of head structures, adult intestinal polyposis, hepatocellular carcinomas, liver zonation, and the development of natural killer cells. Furthermore, we identify a homozygous Apc allele combination with Wnt/β-catenin signaling capacity similar to that in the germline of the Apcmin mice, where somatic Apc loss-of-heterozygosity triggers intestinal polyposis, to distinguish whether co-morbidities in Apcmin mice arise independently of intestinal tumorigenesis. Together, the present genotype–phenotype analysis suggests tissue-specific response levels for the Wnt/β-catenin pathway that regulate both physiological and pathophysiological conditions.
Vyšlo v časopise:
Genetic Dissection of Differential Signaling Threshold Requirements for the Wnt/β-Catenin Pathway. PLoS Genet 6(1): e32767. doi:10.1371/journal.pgen.1000816
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000816
Souhrn
Contributions of null and hypomorphic alleles of Apc in mice produce both developmental and pathophysiological phenotypes. To ascribe the resulting genotype-to-phenotype relationship unambiguously to the Wnt/β-catenin pathway, we challenged the allele combinations by genetically restricting intracellular β-catenin expression in the corresponding compound mutant mice. Subsequent evaluation of the extent of resulting Tcf4-reporter activity in mouse embryo fibroblasts enabled genetic measurement of Wnt/β-catenin signaling in the form of an allelic series of mouse mutants. Different permissive Wnt signaling thresholds appear to be required for the embryonic development of head structures, adult intestinal polyposis, hepatocellular carcinomas, liver zonation, and the development of natural killer cells. Furthermore, we identify a homozygous Apc allele combination with Wnt/β-catenin signaling capacity similar to that in the germline of the Apcmin mice, where somatic Apc loss-of-heterozygosity triggers intestinal polyposis, to distinguish whether co-morbidities in Apcmin mice arise independently of intestinal tumorigenesis. Together, the present genotype–phenotype analysis suggests tissue-specific response levels for the Wnt/β-catenin pathway that regulate both physiological and pathophysiological conditions.
Zdroje
1. KlausA
BirchmeierW
2008 Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8 387 398
2. CleversH
2006 Wnt/beta-catenin signaling in development and disease. Cell 127 469 480
3. MukhopadhyayM
ShtromS
Rodriguez-EstebanC
ChenL
TsukuiT
2001 Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell 1 423 434
4. SatohW
GotohT
TsunematsuY
AizawaS
ShimonoA
2006 Sfrp1 and Sfrp2 regulate anteroposterior axis elongation and somite segmentation during mouse embryogenesis. Development 133 989 999
5. PopperlH
SchmidtC
WilsonV
HumeCR
DoddJ
1997 Misexpression of Cwnt8C in the mouse induces an ectopic embryonic axis and causes a truncation of the anterior neuroectoderm. Development 124 2997 3005
6. HuelskenJ
VogelR
BrinkmannV
ErdmannB
BirchmeierC
2000 Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol 148 567 578
7. MoserAR
ShoemakerAR
ConnellyCS
ClipsonL
GouldKA
1995 Homozygosity for the Min allele of Apc results in disruption of mouse development prior to gastrulation. Dev Dyn 203 422 433
8. ChazaudC
RossantJ
2006 Disruption of early proximodistal patterning and AVE formation in Apc mutants. Development 133 3379 3387
9. LewisSL
KhooPL
De YoungRA
SteinerK
WilcockC
2008 Dkk1 and Wnt3 interact to control head morphogenesis in the mouse. Development 135 1791 1801
10. MiyakiM
KonishiM
Kikuchi-YanoshitaR
EnomotoM
IgariT
1994 Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 54 3011 3020
11. MiyoshiY
AndoH
NagaseH
NishishoI
HoriiA
1992 Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A 89 4452 4456
12. PowellSM
ZilzN
Beazer-BarclayY
BryanTM
HamiltonSR
1992 APC mutations occur early during colorectal tumorigenesis. Nature 359 235 237
13. LammiL
ArteS
SomerM
JarvinenH
LahermoP
2004 Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 74 1043 1050
14. LiuW
DongX
MaiM
SeelanRS
TaniguchiK
2000 Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat Genet 26 146 147
15. PolakisP
2000 Wnt signaling and cancer. Genes Dev 14 1837 1851
16. McCartneyBM
NathkeIS
2008 Cell regulation by the Apc protein Apc as master regulator of epithelia. Curr Opin Cell Biol 20 186 193
17. SmitsR
KielmanMF
BreukelC
ZurcherC
NeufeldK
1999 Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes Dev 13 1309 1321
18. SansomOJ
MenielVS
MuncanV
PhesseTJ
WilkinsJA
2007 Myc deletion rescues Apc deficiency in the small intestine. Nature 446 676 679
19. LiQ
IshikawaTO
OshimaM
TaketoMM
2005 The threshold level of adenomatous polyposis coli protein for mouse intestinal tumorigenesis. Cancer Res 65 8622 8627
20. KielmanMF
RindapaaM
GasparC
van PoppelN
BreukelC
2002 Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling. Nat Genet 32 594 605
21. AlbuquerqueC
BreukelC
van der LuijtR
FidalgoP
LageP
2002 The ‘just-right’ signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. Hum Mol Genet 11 1549 1560
22. MoserAR
PitotHC
DoveWF
1990 A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247 322 324
23. ShibataH
ToyamaK
ShioyaH
ItoM
HirotaM
1997 Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 278 120 123
24. MunemitsuS
AlbertI
SouzaB
RubinfeldB
PolakisP
1995 Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A 92 3046 3050
25. Kimura-YoshidaC
NakanoH
OkamuraD
NakaoK
YonemuraS
2005 Canonical Wnt signaling and its antagonist regulate anterior-posterior axis polarization by guiding cell migration in mouse visceral endoderm. Dev Cell 9 639 650
26. MatsuoI
SudaY
YoshidaM
UekiT
KimuraC
1997 Otx and Emx functions in patterning of the vertebrate rostral head. Cold Spring Harb Symp Quant Biol 62 545 553
27. ZhongW
2008 Going nuclear is again a winning (Wnt) strategy. Dev Cell 15 635 636
28. GurleyKA
RinkJC
Sanchez AlvaradoA
2008 Beta-catenin defines head versus tail identity during planarian regeneration and homeostasis. Science 319 323 327
29. LewisSL
KhooPL
Andrea De YoungR
BildsoeH
WakamiyaM
2007 Genetic interaction of Gsc and Dkk1 in head morphogenesis of the mouse. Mech Dev 124 157 165
30. HoangBH
ThomasJT
Abdul-KarimFW
CorreiaKM
ConlonRA
1998 Expression pattern of two Frizzled-related genes, Frzb-1 and Sfrp-1, during mouse embryogenesis suggests a role for modulating action of Wnt family members. Dev Dyn 212 364 372
31. LuongoC
MoserAR
GledhillS
DoveWF
1994 Loss of Apc+ in intestinal adenomas from Min mice. Cancer Res 54 5947 5952
32. ShoemakerAR
LuongoC
MoserAR
MartonLJ
DoveWF
1997 Somatic mutational mechanisms involved in intestinal tumor formation in Min mice. Cancer Res 57 1999 2006
33. OshimaM
OshimaH
KobayashiM
TsutsumiM
TaketoMM
1995 Evidence against dominant negative mechanisms of intestinal polyp formation by Apc gene mutations. Cancer Res 55 2719 2722
34. PollardP
DeheragodaM
SegditsasS
LewisA
RowanA
2009 The Apc 1322T mouse develops severe polyposis associated with submaximal nuclear beta-catenin expression. Gastroenterology 136: 2204-2213 e2201-2213
35. de La CosteA
RomagnoloB
BilluartP
RenardCA
BuendiaMA
1998 Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A 95 8847 8851
36. SatohS
DaigoY
FurukawaY
KatoT
MiwaN
2000 AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 24 245 250
37. TaniguchiK
RobertsLR
AdercaIN
DongX
QianC
2002 Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 21 4863 4871
38. HirschmanBA
PollockBH
TomlinsonGE
2005 The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr 147 263 266
39. BenhamoucheS
DecaensT
GodardC
ChambreyR
RickmanDS
2006 Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell 10 759 770
40. ColnotS
DecaensT
Niwa-KawakitaM
GodardC
HamardG
2004 Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci U S A 101 17216 17221
41. HaradaN
MiyoshiH
MuraiN
OshimaH
TamaiY
2002 Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin. Cancer Res 62 1971 1977
42. HaradaN
OshimaH
KatohM
TamaiY
OshimaM
2004 Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations. Cancer Res 64 48 54
43. GossKH
RisingerMA
KordichJJ
SanzMM
StraughenJE
2002 Enhanced tumor formation in mice heterozygous for Blm mutation. Science 297 2051 2053
44. HughesTA
BradyHJ
2005 Expression of axin2 is regulated by the alternative 5′-untranslated regions of its mRNA. J Biol Chem 280 8581 8588
45. RebouissouS
AmessouM
CouchyG
PoussinK
ImbeaudS
2009 Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457 200 204
46. BurkeZD
ReedKR
PhesseTJ
SansomOJ
ClarkeAR
2009 Liver zonation occurs through a beta-catenin-dependent, c-Myc-independent mechanism. Gastroenterology 136: 2316-2324 e2311-2313
47. BraeuningA
IttrichC
KohleC
BuchmannA
SchwarzM
2007 Zonal gene expression in mouse liver resembles expression patterns of Ha-ras and beta-catenin mutated hepatomas. Drug Metab Dispos 35 503 507
48. ReyaT
DuncanAW
AillesL
DomenJ
SchererDC
2003 A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423 409 414
49. ColettaPL
MullerAM
JonesEA
MuhlB
HolwellS
2004 Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis. Blood 103 1050 1058
50. IshikawaTO
TamaiY
LiQ
OshimaM
TaketoMM
2003 Requirement for tumor suppressor Apc in the morphogenesis of anterior and ventral mouse embryo. Dev Biol 253 230 246
51. SamuelMS
SuzukiH
BuchertM
PutoczkiTL
TebbuttNC
2009 Elevated Dnmt3a Activity Promotes Polyposis in Apc(Min) Mice by Relaxing Extracellular Restraints on Wnt Signaling. Gastroenterology.
52. GasparC
FrankenP
MolenaarL
BreukelC
van der ValkM
2009 A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis. PLoS Genet 5 e1000547 doi:10.1371/journal.pgen.1000547
53. IshitaniT
KishidaS
Hyodo-MiuraJ
UenoN
YasudaJ
2003 The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Mol Cell Biol 23 131 139
54. JustmanQA
SerberZ
FerrellJEJr
El-SamadH
ShokatKM
2009 Tuning the activation threshold of a kinase network by nested feedback loops. Science 324 509 512
55. JenkinsBJ
GrailD
NheuT
NajdovskaM
WangB
2005 Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat Med 11 845 852
56. HuelskenJ
VogelR
ErdmannB
CotsarelisG
BirchmeierW
2001 beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105 533 545
57. HalfordMM
ArmesJ
BuchertM
MeskenaiteV
GrailD
2000 Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nat Genet 25 414 418
58. MarettoS
CordenonsiM
DupontS
BraghettaP
BroccoliV
2003 Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors. Proc Natl Acad Sci U S A 100 3299 3304
59. BurkeZD
ShenCN
RalphsKL
ToshD
2006 Characterization of liver function in transdifferentiated hepatocytes. J Cell Physiol 206 147 159
60. SansomOJ
ReedKR
HayesAJ
IrelandH
BrinkmannH
2004 Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18 1385 1390
61. FrommerM
McDonaldLE
MillarDS
CollisCM
WattF
1992 A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci U S A 89 1827 1831
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2010 Číslo 1
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- A Major Role of the RecFOR Pathway in DNA Double-Strand-Break Repair through ESDSA in
- Kidney Development in the Absence of and Requires
- The Werner Syndrome Protein Functions Upstream of ATR and ATM in Response to DNA Replication Inhibition and Double-Strand DNA Breaks
- Alternative Epigenetic Chromatin States of Polycomb Target Genes