Abstract
The neuroplastic mechanism of sex reversal in the fish brain remains unclear due to the difficulty in identifying the key neurons involved. Mozambique tilapia show different reproductive behaviours between sexes; males build circular breeding nests while females hold and brood fertilized eggs in their mouth. In tilapia, gonadotropin-releasing hormone 3 (GnRH3) neurons, located in the terminal nerve, regulate male reproductive behaviour. Mature males have more GnRH3 neurons than mature females, and these neurons have been indicated to play a key role in the androgen-induced female-to-male sex reversal of the brain. We aimed to elucidate the signalling pathway involved in the androgen-induced increase in GnRH3 neurons in mature female tilapia. Applying inhibitors to organotypic cultures of brain slices, we showed that the insulin-like growth factor (IGF)-1 receptor (IGF-1R)/PI3K/AKT/mTOR pathway contributed to the androgen-induced increase in GnRH3 neurons. The involvement of IGF-1 and IGF-1R in 11-ketotestosterone (11-KT)-induced development of GnRH3 neurons was supported by an increase in Igf-1 mRNA shortly after 11-KT treatment, the increase of GnRH3 neurons after IGF-1 treatment and the expression of IGF-1R in GnRH3 neurons. Our findings highlight the involvement of IGF-1 and its downstream signalling pathway in the sex reversal of the tilapia brain.
Highlights
Sex reversal is a well-known phenomenon in teleost fish
According to the present results obtained with the terminal nerve (TN)-containing brain slices of mature females (Fig. 2), the in vitro treatment with 11-KT increased the number of gonadotropin-releasing hormone 3 (GnRH3) neurons, indicating that 11-KT can increase the number of GnRH3 neurons without mediation via other organs, such as the gonad and liver
Our hypothesis is strongly supported by the following four findings: (1) Treatment with insulin-like growth factor (IGF)-1 increased the number of GnRH3 neurons (Fig. 3). (2) The expression of IGF-1 mRNA increased shortly after 11-KT treatment (Fig. 4). (3) The potent IGF-1R inhibitor, BMS-754807, strongly suppressed the 11-KT-induced increase of GnRH3 neurons (Fig. 5). (4) Immunohistochemical staining with anti-GnRH3 and anti-IGF-1R antibodies revealed the co-localization of IGF-1R and GnRH3 (Fig. 6)
Summary
Sex reversal is a well-known phenomenon in teleost fish. Some teleosts naturally change their phenotypic sex during their lifetime, while others change it in response to environmental factors or treatments with h ormones[1–3]. The regulatory mechanism related to sex reversal in the brain depends on the type of key stimuli that induce it These and other differences, such as the timing of sex reversal (e.g., during development or after maturation), make it difficult to identify the molecular and neuronal mechanisms of sex reversal in different species. Female and male tilapia exhibit vastly different reproductive behaviours; males fight each other and build a large circular breeding nest, while females hold and brood fertilized eggs in their mouth (mouth brooding) Treatments with androgens, such as a fish natural androgen 11-ketotestosterone (11-KT), were reported to induce male-specific reproductive behaviours in most mature females within two weeks, while their gonads still contained numerous vitellogenic oocytes and the plasma concentration of 17β-estradiol (E2) remained high[14]. Tilapia is a suitable model for investigating the regulatory mechanism of androgen-induced sex reversal in the brain
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