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Wnt signalling in testicular descent: a candidate mechanism for cryptorchidism in Robinow syndrome
George N Harisis1, Nan Chen, Pamela J Farmer
1Douglas Stephens Surgical Research Laboratory, Murdoch Children's Research Institute, Melbourne, Australia.
Background/Aims:
Robinow syndrome is caused by mutations in Wnt-5a or its receptor Ror2 and can lead to cryptorchidism, though the mechanisms are unclear. Wnt-5a knock-out mice fail to undergo gubernacular swelling, similar to insulin-like hormone 3 (INSl-3) knock-out mice. We aimed to characterise Wnt-5a and Ror2 expression in rat gubernacula to better understand how Wnt-5a signalling affects testicular descent.
Methods:
Sprague-Dawley rats (n = 27) were collected with ethics approval (A644) at embryonic days (E) 15, 17, 19 and postnatal day (D) 2. Control and antiandrogen-treated groups were processed for immunohistochemistry for Wnt-5a, Ror2 and β-catenin. Sagittal sections were examined using confocal microscopy.
Results:
Wnt-5a and Ror2 were strongly expressed in the gubernacular bulb at E17 controls, their levels declining at E19 and almost absent by D2. Wnt-5a significantly co-localised with the important transcription factor β-catenin at E17. There was no obvious difference in staining with androgen blockade.
Conclusion:
Wnt-5a, through Ror2 and β-catenin may play a vital role in regulating the gubernacular swelling reaction downstream of INSL-3. Human mutations in Wnt-5a or Ror2 could prevent early gubernacular growth, as suggested by undescended testes in 70% of patients with Robinow Syndrome.
Insights
Wnt-5a signaling, involving Ror2 and beta-catenin, is crucial for gubernacular swelling during testicular descent. Mutations in Wnt-5a or Ror2 may cause cryptorchidism by hindering this early growth.
Area of Science:
- Developmental biology
- Molecular signaling
- Reproductive endocrinology
Background:
- Robinow syndrome, linked to Wnt-5a or Ror2 mutations, can cause cryptorchidism.
- Wnt-5a knockout mice exhibit impaired gubernacular swelling, similar to insulin-like hormone 3 (INSL-3) knockout models.
Purpose of the Study:
- To investigate the expression of Wnt-5a and Ror2 in rat gubernacula.
- To elucidate the role of Wnt-5a signaling in testicular descent.
Main Methods:
- Immunohistochemistry was used to detect Wnt-5a, Ror2, and beta-catenin in rat gubernacula at various embryonic and postnatal days.
- Confocal microscopy analyzed sagittal sections from control and antiandrogen-treated rats.
Main Results:
- Strong expression of Wnt-5a and Ror2 was observed in the gubernacular bulb at embryonic day 17, decreasing by postnatal day 2.
- Wnt-5a significantly co-localized with beta-catenin at embryonic day 17.
- Androgen blockade did not noticeably alter protein staining patterns.
Conclusions:
- Wnt-5a, acting via Ror2 and beta-catenin, likely regulates the gubernacular swelling essential for testicular descent, downstream of INSL-3.
- Defects in Wnt-5a or Ror2 may impede early gubernacular development, potentially explaining undescended testes in Robinow Syndrome patients.
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