Skip to main content
Article thumbnail
Location of Repository

Genetic dissection of differential signaling threshold requirements for the Wnt/β-catenin pathway in vivo

By R. Nusse, M. Buchert, D. Athineos, H.E. Abud, Z.D. Burke, M.C. Faux, M.S. Samuel, A.G. Jarnicki, C.E. Winbanks, I.P. Newton, V.S. Meniel, H. Suzuki, S.A. Stacker, I.S. Näthke, D. Tosh, J. Huelsken, A.R. Clarke, J.K. Heath, O.J. Sansom and M. Ernst

Abstract

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/beta-catenin pathway, we challenged the allele combinations by genetically restricting intracellular beta-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/beta-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/beta-catenin signaling capacity similar to that in the germline of the Apc(min) mice, where somatic Apc loss-of-heterozygosity triggers intestinal polyposis, to distinguish whether co-morbidities in Apc(min) mice arise independently of intestinal tumorigenesis. Together, the present genotype phenotype analysis suggests tissue-specific response levels for the Wnt/beta-catenin pathway that regulate both physiological and pathophysiological conditions

Publisher: Public Library of Science
Year: 2010
OAI identifier: oai:eprints.gla.ac.uk:39452
Provided by: Enlighten

Suggested articles

Citations

  1. (1990). A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. doi
  2. (1992). A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. doi
  3. (2003). A role for Wnt signalling in self-renewal of haematopoietic stem cells. doi
  4. (2009). A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis. doi
  5. (2002). Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling. doi
  6. (1992). APC mutations occur early during colorectal tumorigenesis. doi
  7. (2006). Apc tumor suppressor gene is the ‘‘zonation-keeper’’ of mouse liver. doi
  8. (2000). AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virusmediated transfer of AXIN1. doi
  9. (2001). betaCatenin controls hair follicle morphogenesis and stem cell differentiation in the skin. doi
  10. (2005). Canonical Wnt signaling and its antagonist regulate anterior-posterior axis polarization by guiding cell migration in mouse visceral endoderm. doi
  11. (2008). Cell regulation by the Apc protein Apc as master regulator of epithelia. doi
  12. (1994). Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. doi
  13. (2006). Characterization of liver function in transdifferentiated hepatocytes. doi
  14. (2001). Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. doi
  15. (2006). Disruption of early proximodistal patterning and AVE formation in Apc mutants. doi
  16. (2002). Enhanced tumor formation in mice heterozygous for Blm mutation.
  17. (1995). Evidence against dominant negative mechanisms of intestinal polyp formation by Apc gene mutations.
  18. (2005). Expression of axin2 is regulated by the alternative 59-untranslated regions of its mRNA. doi
  19. (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. doi
  20. (2009). Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. doi
  21. (1992). Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. doi
  22. (2008). Going nuclear is again a winning (Wnt) strategy. doi
  23. (2004). Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations. doi
  24. (1995). Homozygosity for the Min allele of Apc results in disruption of mouse development prior to gastrulation. doi
  25. (2002). Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin.
  26. (2009). Liver zonation occurs through a beta-catenin-dependent, c-Myc-independent mechanism. doi
  27. (2004). Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. doi
  28. (2004). Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. doi
  29. (1994). Loss of Apc+ in intestinal adenomas from Min mice.
  30. (2004). Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis. doi
  31. (2003). Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors. doi
  32. (1997). Misexpression of Cwnt8C in the mouse induces an ectopic embryonic axis and causes a truncation of the anterior neuroectoderm.
  33. (2002). Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. doi
  34. (2000). Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. doi
  35. (2004). Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. doi
  36. (2007). Myc deletion rescues Apc deficiency in the small intestine. doi
  37. (1997). Otx and Emx functions in patterning of the vertebrate rostral head.
  38. (2005). promotes gastric hyperproliferation and desensitizes TGF-beta signaling. doi
  39. (1997). Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. doi
  40. (1995). Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumorsuppressor protein. doi
  41. (2000). Requirement for beta-catenin in anterior-posterior axis formation in mice. doi
  42. (2003). Requirement for tumor suppressor Apc in the morphogenesis of anterior and ventral mouse embryo. doi
  43. (2000). Rykdeficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk.
  44. (2008). Sanchez Alvarado A
  45. (2006). Shimono A
  46. (1997). Somatic mutational mechanisms involved in intestinal tumor formation in Min mice.
  47. (1998). Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. doi
  48. (2002). The ‘just-right’ signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. doi
  49. (2009). The Apc 1322T mouse develops severe polyposis associated with submaximal nuclear beta-catenin expression. doi
  50. (2005). The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. doi
  51. (2003). The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/ Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. doi
  52. (2005). The threshold level of adenomatous polyposis coli protein for mouse intestinal tumorigenesis. doi
  53. (2009). Tuning the activation threshold of a kinase network by nested feedback loops. doi
  54. (2000). Wnt signaling and cancer. doi
  55. (2008). Wnt signalling and its impact on development and cancer. doi
  56. (2006). Wnt/beta-catenin signaling in development and disease. doi
  57. (2007). Zonal gene expression in mouse liver resembles expression patterns of Ha-ras and betacatenin mutated hepatomas. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.