Abstract
During kidney development, canonical Wnt signaling activates differentiation, while the transcription factor Six2 maintains the progenitor pool. These opposing signals help to regulate nephron formation and ensure the full complement of nephrons are formed. Since these two factors control differing fates in kidney mesenchyme, we hypothesized that overexpression of Wnt9b in Six2-expressing cells would disrupt kidney formation and may alter cell differentiation decisions in other tissues. We created a transgenic mouse that conditionally expressed the canonical Wnt ligand in the developing kidney, Wnt9b. The transgene is activated by cre recombinase and expresses GFP. We first tested its biological activity using Hoxb7-cre and found that transgenic Wnt9b was capable of inducing differentiation genes and of rescuing kidney development in Wnt9b−/− homozygous deficient mice. In contrast, expression of Wnt9b in cells using Six2-cre caused gastrointestinal distress and severe renal failure in adult mice. Transgenic kidneys had numerous cystic tubules and elevated creatinine values (0.652±0.044) compared to wild-type mice (0.119±0.002). These animals also exhibited a malformed pyloric sphincter, duodenogastric reflux, and a transformation of the distal stomach into proximal fate. The gene expression changes observed for the Wnt9b:EGFP transgene were compared to a stabilized β-catenin allele to determine that Wnt9b is activating the canonical Wnt pathway in the tissues analyzed. These results demonstrate that expression of Wnt9b in Six2-positive cells disrupts cell fate decisions in the kidney and the gastrointestinal tract.
Highlights
The canonical Wnt signaling pathway is a key regulator of cell fate, cell proliferation, and cell adhesion during development and throughout adulthood
Transgenic mice express Wnt9b when activated by cre recombinase
The Wnt9b transgene was constructed with a lox-STOP cassette [15] to create a conditionally active Wnt9b that depends on cre recombinase for expression (Fig. 1A)
Summary
The canonical Wnt signaling pathway is a key regulator of cell fate, cell proliferation, and cell adhesion during development and throughout adulthood. The central paradigm is that cytoplasmic bcatenin is sequestered in a destruction complex, phosphorylated by GSK3b, and targeted to the ubiquitin destruction pathway in the absence of a Wnt signal. Numerous mouse models have been created to study this pathway including both gain and loss of function alleles of Wnts, Wnt receptors, b-catenin, and the TCF/ LEF transcriptional regulators. These models have uncovered essential roles for canonical Wnt signaling in bone, hair, intestine, blood, and cancer [2]. An emerging theme from these studies is that many biological processes are acutely sensitive to the strength of canonical Wnt signaling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
