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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

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