Drosophila and different vertebrates have shown that gradients of the Wnt, Hedgehog (Hh)
and transforming growth factor-beta (TGF-β) families of morphogens play critical roles in
limb patterning. Morphogens are often expressed in organizing centres and can act over a long
range to coordinate the patterning of an entire field of cells. These observations imply that exposure
to different concentrations of these diffusible factors may trigger differential cellular responses.
In order to study these dosage-dependent Wnt/β-catenin signaling effects, we have
generated several hypomorphic mutant alleles at the mouse
Apc locus and studied their cellular and phenotypic outcomes in stem cell renewal and differentiation, and in tumorigenesis. The
results clearly show that Apc mutations differentially affect the capacity of stem cells to differentiate
in a dosage-dependent fashion. Likewise, different
Apc mutations (and the corresponding Wnt signaling dosages) confer different degrees of susceptibility to tumorigenesis in the
corresponding mouse models. These results have implications for the understanding of the molecular
and cellular basis of tumor initiation by defects in the Wnt pathway. We propose a model in which
adult somatic stem cell compartments are characterized by tissue-specific
β-catenin threshold levels for cell proliferation, differentiation and apoptosis. Different
APC mutations will result in different levels of
β-catenin signaling, thus conferring different degrees of tumor susceptibility in
different tissues. Hence, β-catenin dosage - dependent effects may not only explain how a single
pathway is involved in the development and homeostasis of different tissues, but also its pleiotrophic
role in tumorigenesis.
" />
Drosophila and different vertebrates have shown that gradients of the Wnt, Hedgehog (Hh)
and transforming growth factor-beta (TGF-β) families of morphogens play critical roles in
limb patterning. Morphogens are often expressed in organizing centres and can act over a long
range to coordinate the patterning of an entire field of cells. These observations imply that exposure
to different concentrations of these diffusible factors may trigger differential cellular responses.
In order to study these dosage-dependent Wnt/β-catenin signaling effects, we have
generated several hypomorphic mutant alleles at the mouse
Apc locus and studied their cellular and phenotypic outcomes in stem cell renewal and differentiation, and in tumorigenesis. The
results clearly show that Apc mutations differentially affect the capacity of stem cells to differentiate
in a dosage-dependent fashion. Likewise, different
Apc mutations (and the corresponding Wnt signaling dosages) confer different degrees of susceptibility to tumorigenesis in the
corresponding mouse models. These results have implications for the understanding of the molecular
and cellular basis of tumor initiation by defects in the Wnt pathway. We propose a model in which
adult somatic stem cell compartments are characterized by tissue-specific
β-catenin threshold levels for cell proliferation, differentiation and apoptosis. Different
APC mutations will result in different levels of
β-catenin signaling, thus conferring different degrees of tumor susceptibility in
different tissues. Hence, β-catenin dosage - dependent effects may not only explain how a single
pathway is involved in the development and homeostasis of different tissues, but also its pleiotrophic
role in tumorigenesis.
" />
Drosophila and different vertebrates have shown that gradients of the Wnt, Hedgehog (Hh)
and transforming growth factor-beta (TGF-β) families of morphogens play critical roles in
limb patterning. Morphogens are often expressed in organizing centres and can act over a long
range to coordinate the patterning of an entire field of cells. These observations imply that exposure
to different concentrations of these diffusible factors may trigger differential cellular responses.
In order to study these dosage-dependent Wnt/β-catenin signaling effects, we have
generated several hypomorphic mutant alleles at the mouse
Apc locus and studied their cellular and phenotypic outcomes in stem cell renewal and differentiation, and in tumorigenesis. The
results clearly show that Apc mutations differentially affect the capacity of stem cells to differentiate
in a dosage-dependent fashion. Likewise, different
Apc mutations (and the corresponding Wnt signaling dosages) confer different degrees of susceptibility to tumorigenesis in the
corresponding mouse models. These results have implications for the understanding of the molecular
and cellular basis of tumor initiation by defects in the Wnt pathway. We propose a model in which
adult somatic stem cell compartments are characterized by tissue-specific
β-catenin threshold levels for cell proliferation, differentiation and apoptosis. Different
APC mutations will result in different levels of
β-catenin signaling, thus conferring different degrees of tumor susceptibility in
different tissues. Hence, β-catenin dosage - dependent effects may not only explain how a single
pathway is involved in the development and homeostasis of different tissues, but also its pleiotrophic
role in tumorigenesis.
" />
APC dosage effects in tumorigenesis and stem cell differentiation
Published: 1 September 2004
Claudia Gaspar and Riccardo Fodde
Dept. of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Abstract
It is well established that concentration gradients of signaling molecules (the
so-called "morphogens") organize and pattern tissues in developing animals. In particular,
studies in Drosophila and different vertebrates have shown that gradients of the Wnt, Hedgehog (Hh)
and transforming growth factor-beta (TGF-β) families of morphogens play critical roles in
limb patterning. Morphogens are often expressed in organizing centres and can act over a long
range to coordinate the patterning of an entire field of cells. These observations imply that exposure
to different concentrations of these diffusible factors may trigger differential cellular responses.
In order to study these dosage-dependent Wnt/β-catenin signaling effects, we have
generated several hypomorphic mutant alleles at the mouse
Apc locus and studied their cellular and phenotypic outcomes in stem cell renewal and differentiation, and in tumorigenesis. The
results clearly show that Apc mutations differentially affect the capacity of stem cells to differentiate
in a dosage-dependent fashion. Likewise, different
Apc mutations (and the corresponding Wnt signaling dosages) confer different degrees of susceptibility to tumorigenesis in the
corresponding mouse models. These results have implications for the understanding of the molecular
and cellular basis of tumor initiation by defects in the Wnt pathway. We propose a model in which
adult somatic stem cell compartments are characterized by tissue-specific
β-catenin threshold levels for cell proliferation, differentiation and apoptosis. Different
APC mutations will result in different levels of
β-catenin signaling, thus conferring different degrees of tumor susceptibility in
different tissues. Hence, β-catenin dosage - dependent effects may not only explain how a single
pathway is involved in the development and homeostasis of different tissues, but also its pleiotrophic
role in tumorigenesis.