Igf3 activates β-catenin signaling to stimulate spermatogonial differentiation in zebrafish

in Journal of Endocrinology
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Follicle-stimulating hormone (Fsh) is a major regulator of spermatogenesis, targeting somatic cell functions in the testes. We reported previously that zebrafish Fsh promoted the differentiation of type A undifferentiated spermatogonia (Aund) by stimulating the production of factors that advance germ cell differentiation, such as androgens, insulin-like peptide 3 (Insl3) and insulin-like growth factor 3 (Igf3). In addition, Fsh also modulated the transcript levels of several other genes, including some belonging to the Wnt signaling pathway. Here, we evaluated if and how Fsh utilizes part of the canonical Wnt pathway to regulate the development of spermatogonia. We quantified the proliferation activity and relative section areas occupied by Aund and type A differentiating (Adiff) spermatogonia and we analyzed the expression of selected genes in response to recombinant proteins and pharmacological inhibitors. We found that from the three downstream mediators of Fsh activity we examined, Igf3, but not 11-ketotestosterone or Insl3, modulated the transcript levels of two β-catenin sensitive genes (cyclinD1 and axin2). Using a zebrafish β-catenin signaling reporter line, we showed that Igf3 activated β-catenin signaling in type A spermatogonia and that this activation did not depend on the release of Wnt ligands. Pharmacological inhibition of the β-catenin or of the phosphoinositide 3-kinase (PI3K) pathways revealed that Igf3 activated β-catenin signaling in a manner involving PI3K to promote the differentiation of Aund to Adiff spermatogonia. This mechanism represents an intriguing example for a pituitary hormone like Fsh using Igf signaling to recruit the evolutionary conserved, local β-catenin signaling pathway to regulate spermatogenesis.

 

      Society for Endocrinology

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    Igf3 activates β-catenin-dependent signaling in type A spermatogonia. (A) Transcript levels of two β-catenin sensitive genes (cyclinD1 and axin2) in basal conditions (dotted line; control condition) or in the presence of 11-KT (200 nM, sample size (n = 6), Insl3 (100 ng/mL, n = 10) or Igf3 (100 ng/mL, n = 7), represented by bars. (B) Transcript levels of cyclinD1 and axin2 in the presence of Fsh (100 ng/mL) (dotted line; control condition) or in combination with the inhibitor of Igf1r NVP-AEW541 (10 µM, n = 7), represented by bars. The quantification cycles (Cq) of the reference gene (elf1a) are shown in the inset. Results are presented as fold change with respect to the control group (basal or 100 ng/mL Fsh, respectively) Asterisks indicate significant differences (P < 0.05) to the respective control group. (C, D, E, F, G and H) Immunocytochemical detection of Gfp in testis sections from transgenic (7xTCF-Xla.Siam:GFP)ia4 zebrafish incubated for 3 h under basal conditions or in the presence of Igf3 (100 ng/mL, n = 3). A full color version of this figure is available at https://doi.org/10.1530/JOE-18-0124.

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    Igf3 activates β-catenin-dependent signaling in a Wnt ligand-independent manner. (A, B, C, D, E and F) Immunocytochemical detection of Gfp in testis sections from transgenic (7xTCF-Xla.Siam:GFP)ia4 zebrafish incubated for 3 h in the presence of IWP-12 (50 µM) alone, or in combination with 100 ng/mL Igf3 (n = 3). Nuclear DNA was stained with propidium iodide (PI). (G) BrdU-labeling indices of type Aund and type Adiff spermatogonia in basal conditions (n = 7) or in the presence of Igf3 (100 ng/mL, n = 12) with or without IWP-12 (50 µM, n = 5) after 5 days of incubation. (H) Proportion of area occupied by type Aund and type Adiff spermatogonia in basal conditions (n = 7) or in the presence of Igf3 (100 ng/mL, n = 12) with or without IWP-12 (50 µM, n = 5) after 5 days of incubation. (I) Western blot and (J) densitometric analysis of Gfp production in testis sections from transgenic (7xTCF-Xla.Siam:GFP)ia4 zebrafish incubated for 3 days in basal conditions or in the presence of IWP-12 (50 µM) (n = 3). Letters and asterisk indicate significant differences (P < 0.05) among groups. A full color version of this figure is available at https://doi.org/10.1530/JOE-18-0124.

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    Igf3 uses β-catenin signaling to stimulate the differentiation of type A spermatogonia. (A) BrdU incorporation of type Aund and type Adiff spermatogonia in basal conditions (n = 6), in the presence of Igf3 (100 ng/mL) alone (n = 21), or in the additional presence of either XAV939 (10 µM; n = 7) or IWR-1 (12 µM; n = 8). (B) Proportion of section surface area occupied by cysts containing type Aund and type Adiff spermatogonia in basal conditions (n = 5), in the presence of Igf3 (100 ng/mL) alone (n = 21), or in the additional presence of XAV939 (10 µM; n = 7) or of IWR-1 (12 µM; n = 9). (C, D, E, F, G and H) Immunofluorescent detection of Gfp in sections of zebrafish testis in the presence of Igf3 (100 ng/mL) alone (C, D and E) or in combination with XAV939 (10 µM; F, G and H) after 3 h of incubation (n = 3). Nuclear DNA was stained with propidium iodide (PI). (I) Gene expression analysis of two β-catenin sensitive genes (cyclinD1 and axin2) and germ cell marker genes in adult zebrafish testis after 5 days of tissue culture in the presence of Igf3 (100 ng/mL; dotted line; control condition) alone or in combination with 10 µM XAV939 (represented by bars; n = 8). The quantification cycles (Cq) of the reference gene (elf1a) are shown in the inset. Results are presented as percentage (A and B) or as fold changes with respect to the control group (100 ng/mL Igf3) (I). Letters indicate significant differences among groups (P < 0.05), asterisks (*P < 0.05; **P < 0.01) indicate significant differences to the control condition. A full color version of this figure is available at https://doi.org/10.1530/JOE-18-0124.

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    Testicular igf1 receptor expression and MAPK and PI3K inhibitor effects on an Igf3-stimulated differentiation of type A spermatogonia. (A and B) Localization of igf1ra (A) and igf1rb (B) transcripts by in situ hybridization using adult zebrafish testis cryosections. Black arrows show staining in SCs and their extension surrounding spermatogonia; red arrows in (B) show staining in spermatogonia. Insets in A and B show the absence of specific labeling when using sense probes. (C and D) Transcript levels of two β-catenin sensitive genes (cyclinD1 and axin2) and germ cell marker genes in the presence of Igf3 (100 ng/mL) alone (the control condition of these experiments, represented by a dotted line) or in the presence of Igf3 in combination with the MAPK inhibitor PD98059 (C; 50 µM; n = 10; represented by bars), or the PI3K inhibitor LY294002 (D; 20 µM; n = 8; represented by bars). The quantification cycles (Cq) of the reference gene (elf1a) are shown in the insets. (E) BrdU-labeling indices of type Aund and type Adiff spermatogonia in the presence of Igf3 (100 ng/mL; control condition, represented by the dotted line) alone or in combination with the PI3K inhibitor LY294002 (20 µM; n = 5; represented by bars). (F) Proportion of section surface area occupied by cysts containing type Aund and type Adiff spermatogonia in the presence of Igf3 (100 ng/mL; control condition, represented by the dotted line) alone or in combination with the PI3K inhibitor LY294002 (20 µM; n = 5; represented by bars). (G and H) Immunocytochemical detection of BrdU in sections of zebrafish testis incubated in the presence of 100 ng/mL Igf3 alone (G) or in combination with the PI3K inhibitor LY294002 (H; 20 µM) for 5 days, showing BrdU-positive (+) and -negative (−) Aund and Adiff spermatogonia. Results are presented as fold changes with respect to the control group (100 ng/mL Igf3). Asterisks indicate significant differences (*P < 0.05; **P < 0.01) to the respective control group that were incubated with Igf3 (100 ng/mL) alone. A full color version of this figure is available at https://doi.org/10.1530/JOE-18-0124.

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    Effect of Igf3 on the proliferation of Sertoli cells contacting type A spermatogonia. Immunocytochemical detection of BrdU in sections of zebrafish testis showing free BrdU-positive SCs (A), BrdU-positive SCs contacting BrdU-negative (−) (B) and -positive (+) (C) Aund and contacting BrdU-positive (+) Adiff spermatogonia (D). Number of BrdU-positive free Sertoli cells, Sertoli cells contacting BrdU-negative and -positive Aund, and Sertoli cells contacting Adiff in basal conditions (dotted line) or in the presence of the presence of Igf3 (100 ng/mL; represented by bars; n = 7) (E) or in the presence of Igf3 (100 ng/mL; dotted line; control condition) with or without 10 µM XAV939 (represented by bars; n = 7) (F) or 20 µM LY294002 (n = 8; represented by bars) (G). A full color version of this figure is available at https://doi.org/10.1530/JOE-18-0124.

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    Schematic representation of the effects of Igf3 on spermatogenesis by modulating canonical Wnt signaling. Fsh-stimulated Igf3 stimulates differentiating divisions of spermatogonia by increasing Igf3 release from Sertoli cells, which activates β-catenin-dependent, canonical Wnt signaling. A full color version of this figure is available at https://doi.org/10.1530/JOE-18-0124.

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