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Cryptorchidism Clues: Molecular signals regulate cremaster muscle formation
Jaya Vikraman, MBBS1, Maciej Szarek, Bachelor of Science2, Ruili Li, PhD3, Francisco Lopez-Marambio, Bachelor of Science3, Bridget Southwell, PhD1, John M. Hutson, AO, MD, MB, DSc, FRACS, FAAP, Chair Paediatric Sur4.
1University of Melbourne, Department of Paediatrics, Victoria, Australia, 2University of Melbourne, Department of Anatomy and Neuroscience, Victoria, Australia, 3Douglas Stephens Surgical Research Laboratory, Murdoch Childrens Research Institute, Victoria, Australia, 4Royal Children's Hospital, Department of Urology, Victoria, Australia.
The cremaster muscle differentiates during gubernacular migration towards the scrotum, but molecular cues regulating its morphology and influence in cryptorchidism remain elusive. We hypothesize that cremaster myogenesis involves peroxisome proliferator-activated receptor (PPAR) gamma and beta-catenin. PPAR-gamma is a nuclear receptor that acts downstream of insulin-like-hormone 3, which controls the transabdominal stage of testicular descent. Beta-catenin promotes myogenic genes and participates in cellular adhesion and differentiation. We tested whether beta-catenin was regulated by PPAR-gamma in the developing gubernaculum, and if this was androgen dependant.
Gubernacula from untreated male Sprague-Dawley (SD) rats (n=12) or treated with anti-androgen, flutamide (n=12) at E19, D0 and D2 were processed for fluorescent immunohistochemistry. Antibodies against PPAR-gamma and beta-catenin were visualized by confocal microscopy.
PPAR-gamma immunoreactivity (IR) and beta-catenin-IR increased with age in all animals. E19 SD controls had less PPAR-gamma-IR than flutamide-treated animals, in both the progress zone and developing cremaster. By D2, PPAR-gamma-IR moved intranuclear in developing cremaster cells, and androgen blockade caused PPAR-gamma-IR to remain cytoplasmic and co-localize with beta-catenin. Co-localisation of PPAR-gamma-IR and Beta-catenin-IR at cell junctions was also observed in the developing cremaster of D0 and D2 SD animals.
The developing cremaster cells had high PPAR-gamma-IR. Blockade of androgen did not alter the quantitative fluorescence over age groups, however it altered the distribution of PPAR-gamma-IR in cremaster cells. We suggest activated androgen receptors may regulate movement of PPAR-gamma to the nucleus of cremaster cells. Co-localization of cytoplasmic PPAR-gamma and beta-catenin at cell junctions suggests the phosphorylation of beta-catenin, which may be due to the PPAR-gamma led negative feedback loop of the adenomatous polyposis complete product (APC) destruction complex. Abnormalities in PPAR-gamma and beta-catenin signaling may influence testicular descent to cause cryptorchidism.
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