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KCTD13-Mediated Androgen Receptor Signaling in Penile Development
Hunter Flores, BS1, Ahmed Chahdi, PhD2, Marisol O'Neill, PhD3, Juan Bournat, PhD1, Carolina Jorgez, PhD1, Abhishek Seth, MD2.
1Baylor College of Medicine, Houston, TX, USA, 2Nemours Children's Health, Orlando, FL, USA, 3University of California, San Francisco, San Francisco, CA, USA.

Background: We have identified KCTD13 as an important risk factor for congenital genitourinary defects in humans. KCTD13 acts as a substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, which regulates the actin cytoskeleton to modulate cell migration, proliferation, and androgen signaling. We generated a mouse model lacking Kctd13 that has cryptorchidism and micropenis, reduced levels of nuclear androgen receptor (AR) and SOX9, and increased levels of RHOA. Kctd13-mutant mice show an undervirilized genitourinary phenotype, suggesting a disturbance in androgen signaling. We hypothesized that restoration of AR levels in the penis of Kctd13-/- mice rescues the undervirilized phenotype. Methods: To restore AR expression in urethral mesenchyme and understand the role of Kctd13 in penile development, we generated double-knockout (KO) mice that lack Kctd13 and conditionally express AR in the urethral mesenchyme after cre activation with Twistcre (Kctd13-/-; CMV-AR;Twist2cre, herein called double-KO mouse). Penis morphology was determined using microcomputed tomography (μCT) that allows us to perform 3D penile reconstructions for comparison of the genitourinary phenotype of control, Kctd13-/-, and double-KO mice. Fertility was assessed by breeding 10 mice from each genotypic group to a wild-type (WT) female for 6 months, and then comparing litter size, number, and frequency between the groups. Results: Using μCT we established that Kctd13-/- mice have micropenis (2.5 standard deviations (SD) below the mean penile length for the respective age). The average penile length in WT mice was 5.880.16 mm. The length of Kctd13-/- mice penises ranged from 2.90-5.54 mm with 13 penises characterized as micropenis (<5.48 mm) and 60% with a length below 4 mm (11.5 SD). We evaluated additional penile parameters to determine if the global penile development was affected. When compared to WT mice, the male urogenital mating protuberance (MUMP) length was significantly shorter in null mice. The length and base of the baculum (bone in the murine penis) were significantly shorter and narrower, respectively, in null mice compared to those in WT mice. While the penises of mutant mice were smaller, the location of the urethral meatus was similar and orthotopic in location in both mutant and WT penises. When the double-KO mouse was compared to Kctd13-/- mice, we observed an increase in the length of the mesenchyme-derived MUMP, indicating that an increase in androgen signal rescues the micropenis phenotype of Kctd13-/- mice. In addition, the infertility of the double-KO mice was improved, indicating the importance on penile development and fertility. Conclusion: We show that Kctd13-mediated AR loss contributes to micropenis and subfertility in Kctd13-/- mice. Restoration of AR in the penile mesoderm rescues this phenotype as seen in the double-KO mice. We therefore highlight the role of Kctd13 in penile development and demonstrate that micropenis in Kctd13-/- mice results from dysfunction of a specific cell type.


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