ROLE OF WNT11 IN KIDNEY ONTOGENESIS AND DEVELOPMENT OF RENAL ORGANOID BASED MODELS TO IDENTIFY CANDIDATE ONCOGENES, ACTA UNIVERSITATIS OULUENSIS D Medica 1463
|Kustantaja:||Oulun yliopisto|| |
|Sijainti:||Print Tietotalo|| |
|Tekijät:||XU QI|| |
In the kidney, Wnt is involved in ureteric bud branching and nephrogenesis. Wnt mutation may
lead to specific developmental dysfunctions and diseases. As part of this thesis, I show that Wnt11
is expressed in the renal tubules, except for the ureteric epitheliums, and I examine the function of
Wnt11 in renal tubule organization using the new C57Bl6 Wnt11-/- mouse model. Convoluted and
dilated tubules were observed in the Wnt11 mutated kidneys that may cause glomerular cysts and
kidney dysfunction. More specifically, a lack of Wnt11 in the kidney reduced Six2, Hoxd1, and
Hox10 expression, which may have contributed to the anomalies in the kidney tubular system.
Embryogenesis and carcinogenesis share molecular characteristics. Gene expression changes
take place during development to meet the demands of the tissue formation, but ectopic expression
of embryonic genes by deletion, SNPs, or epigenetic modification in adult may lead to cancer. The
research carried out as part of this thesis identified genes that were differentially expressed in both
induced metanephric mesenchymes (MM) and human ccRCC. Gene silencing of Bnip3, Gsn,
Lgals3, Pax8, Cav1, Egfr, and Itgb2 mediated by siRNA inhibited the migration, viability and
invasion capacity of Renca cells (RCC). Furthermore, by using the novel 3D in vitro MM-Renca
co-culture setup, the result revealed that downregulation of Bnip3, Cav1 or Gsn in Renca cells
partly rescued the RCC-mediated inhibition epithelial tubules formation during nephrogenesis.
Altogether, the data demonstrates that renal ontogenesis control genes play a role both in
normal kidney development and in kidney cancer. The 3D RCC-MM chimera organoids
developed as part of the research may also serve as a novel model for kidney cancer study.