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Fgf8-Deficient Mice Compensate for Reduced GnRH Neuronal Population and Exhibit Normal Testicular Function.

Zhang W, Johnson JI, Tsai PS - Front Endocrinol (Lausanne) (2015)

Bottom Line: Our results showed that GnRH neuron numbers were significantly and consistently reduced in Fgf8 Het mice of both sexes in all ages examined, suggesting these animals were born with an inherently defective GnRH system, and no further postnatal loss of GnRH neurons had occurred.Fgf8 Het males also had normal seminal vesicle and testicular mass/body mass ratios, testicular histology, and circulating LH.Overall, our data speak to the extraordinary ability of a GnRH system permanently compromised by developmental defect to overcome pre-existing deficiencies to ensure pubertal progression and reproduction.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder , Boulder, CO , USA.

ABSTRACT
Gonadotropin-releasing hormone (GnRH) is critical for the onset and maintenance of reproduction in vertebrates. The development of GnRH neurons is highly dependent on fibroblast growth factor (Fgf) signaling. Mice with a hypomorphic Fgf8 allele (Fgf8 Het) exhibited a ~50% reduction in GnRH neuron number at birth. Female Fgf8 Het mice were fertile but showed significantly delayed puberty. However, it was unclear if these mice suffered additional loss of GnRH neurons after birth, and if male Fgf8 Het mice had normal pubertal transition and testicular function. In this study, we examined postnatal GnRH neuron number and hypothalamic GnRH content in Fgf8 Het mice from birth to 120 days of age. Further, we examined seminal vesicle and testicular growth, testicular histology, and circulating luteinizing hormone (LH) around and after pubertal transition. Our results showed that GnRH neuron numbers were significantly and consistently reduced in Fgf8 Het mice of both sexes in all ages examined, suggesting these animals were born with an inherently defective GnRH system, and no further postnatal loss of GnRH neurons had occurred. Despite an innately compromised GnRH system, male and female Fgf8 mice exhibited normal levels of immunoassayable hypothalamic GnRH peptide at all ages examined except on 60 days of age, suggesting increased GnRH synthesis or reduced turnover as a compensatory mechanism. Fgf8 Het males also had normal seminal vesicle and testicular mass/body mass ratios, testicular histology, and circulating LH. Overall, our data speak to the extraordinary ability of a GnRH system permanently compromised by developmental defect to overcome pre-existing deficiencies to ensure pubertal progression and reproduction.

No MeSH data available.


Related in: MedlinePlus

Number of GnRH neurons in PN0–120 male (A) and female (B) WT and Fgf8 Het mice. In both sexes, GnRH neuron numbers in Fgf8 Het mice were consistently reduced compared to WT at all ages examined. Each bar = mean ± SEM; N = 5–6. *P < 0.05; **P < 0.01; #P < 0.001; ##P < 0.0001 compared to WT of the same age. (C–F) Representative photomicrographs of GnRH IHC at the plane of OVLT in PN35 WT (C,D) and Fgf8 Het (E,F) male and female mice. Scale bar = 50 μm.
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Figure 1: Number of GnRH neurons in PN0–120 male (A) and female (B) WT and Fgf8 Het mice. In both sexes, GnRH neuron numbers in Fgf8 Het mice were consistently reduced compared to WT at all ages examined. Each bar = mean ± SEM; N = 5–6. *P < 0.05; **P < 0.01; #P < 0.001; ##P < 0.0001 compared to WT of the same age. (C–F) Representative photomicrographs of GnRH IHC at the plane of OVLT in PN35 WT (C,D) and Fgf8 Het (E,F) male and female mice. Scale bar = 50 μm.

Mentions: To examine if postnatal loss of GnRH neurons occurred in Fgf8 Het mice, GnRH neurons in PN0, 10, 20, 25, 30, 35, 60, and 120 male and female mice were analyzed (Figures 1 and 2). For males, two-way ANOVA revealed a significant effect of genotype [F(1, 67) = 152.5; P < 0.0001], age [F(6, 67) = 4.7; P = 0.0005], but no genotype × age interaction [F(6, 67) = 2.2; P = 0.053] on GnRH neuron number in males (Figure 1A). Post hoc test revealed a significant reduction of GnRH neurons in Fgf8 Het males compared to WT males in every age group examined starting at PN0 (Figure 1A). When GnRH neuronal count in Fgf8 Het males was analyzed as percent of GnRH neurons found in age-matched WT males (Figure 2A), Kruskal–Wallis test detected no significant differences across the ages examined (P = 0.14), suggesting Fgf8 deficiency did not contribute to postnatal GnRH neurons loss within the first 120 days of birth. For females, two-way ANOVA revealed a significant effect of genotype [F(1, 68) = 119.4; P < 0.0001], age [F(6, 68) = 3.16; P < 0.0086], but no genotype × age interaction [F(6, 68) = 0.67; P = 0.67] on GnRH neuron number (Figure 1B). Similar to males, post hoc test also revealed a significant reduction of GnRH neurons in Fgf8 Het females compared to WT females in every age group examined (Figure 1B). When GnRH neuronal count in Fgf8 Het females was analyzed as percent of GnRH neurons found in age-matched WT females (Figure 2B), Kruskal–Wallis test, again, detected no significant differences across the ages examined (P = 0.47). Averaging all time points examined, male and female Fgf8 Het mice had 55.3 ± 2.8 and 59.6 ± 2.5%, respectively, of the normal complement of GnRH neurons found in WT controls. Representative images of GnRH neurons near the OVLT in PN35 WT and Fgf8 Het mice are shown (Figures 1C–F).


Fgf8-Deficient Mice Compensate for Reduced GnRH Neuronal Population and Exhibit Normal Testicular Function.

Zhang W, Johnson JI, Tsai PS - Front Endocrinol (Lausanne) (2015)

Number of GnRH neurons in PN0–120 male (A) and female (B) WT and Fgf8 Het mice. In both sexes, GnRH neuron numbers in Fgf8 Het mice were consistently reduced compared to WT at all ages examined. Each bar = mean ± SEM; N = 5–6. *P < 0.05; **P < 0.01; #P < 0.001; ##P < 0.0001 compared to WT of the same age. (C–F) Representative photomicrographs of GnRH IHC at the plane of OVLT in PN35 WT (C,D) and Fgf8 Het (E,F) male and female mice. Scale bar = 50 μm.
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Figure 1: Number of GnRH neurons in PN0–120 male (A) and female (B) WT and Fgf8 Het mice. In both sexes, GnRH neuron numbers in Fgf8 Het mice were consistently reduced compared to WT at all ages examined. Each bar = mean ± SEM; N = 5–6. *P < 0.05; **P < 0.01; #P < 0.001; ##P < 0.0001 compared to WT of the same age. (C–F) Representative photomicrographs of GnRH IHC at the plane of OVLT in PN35 WT (C,D) and Fgf8 Het (E,F) male and female mice. Scale bar = 50 μm.
Mentions: To examine if postnatal loss of GnRH neurons occurred in Fgf8 Het mice, GnRH neurons in PN0, 10, 20, 25, 30, 35, 60, and 120 male and female mice were analyzed (Figures 1 and 2). For males, two-way ANOVA revealed a significant effect of genotype [F(1, 67) = 152.5; P < 0.0001], age [F(6, 67) = 4.7; P = 0.0005], but no genotype × age interaction [F(6, 67) = 2.2; P = 0.053] on GnRH neuron number in males (Figure 1A). Post hoc test revealed a significant reduction of GnRH neurons in Fgf8 Het males compared to WT males in every age group examined starting at PN0 (Figure 1A). When GnRH neuronal count in Fgf8 Het males was analyzed as percent of GnRH neurons found in age-matched WT males (Figure 2A), Kruskal–Wallis test detected no significant differences across the ages examined (P = 0.14), suggesting Fgf8 deficiency did not contribute to postnatal GnRH neurons loss within the first 120 days of birth. For females, two-way ANOVA revealed a significant effect of genotype [F(1, 68) = 119.4; P < 0.0001], age [F(6, 68) = 3.16; P < 0.0086], but no genotype × age interaction [F(6, 68) = 0.67; P = 0.67] on GnRH neuron number (Figure 1B). Similar to males, post hoc test also revealed a significant reduction of GnRH neurons in Fgf8 Het females compared to WT females in every age group examined (Figure 1B). When GnRH neuronal count in Fgf8 Het females was analyzed as percent of GnRH neurons found in age-matched WT females (Figure 2B), Kruskal–Wallis test, again, detected no significant differences across the ages examined (P = 0.47). Averaging all time points examined, male and female Fgf8 Het mice had 55.3 ± 2.8 and 59.6 ± 2.5%, respectively, of the normal complement of GnRH neurons found in WT controls. Representative images of GnRH neurons near the OVLT in PN35 WT and Fgf8 Het mice are shown (Figures 1C–F).

Bottom Line: Our results showed that GnRH neuron numbers were significantly and consistently reduced in Fgf8 Het mice of both sexes in all ages examined, suggesting these animals were born with an inherently defective GnRH system, and no further postnatal loss of GnRH neurons had occurred.Fgf8 Het males also had normal seminal vesicle and testicular mass/body mass ratios, testicular histology, and circulating LH.Overall, our data speak to the extraordinary ability of a GnRH system permanently compromised by developmental defect to overcome pre-existing deficiencies to ensure pubertal progression and reproduction.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder , Boulder, CO , USA.

ABSTRACT
Gonadotropin-releasing hormone (GnRH) is critical for the onset and maintenance of reproduction in vertebrates. The development of GnRH neurons is highly dependent on fibroblast growth factor (Fgf) signaling. Mice with a hypomorphic Fgf8 allele (Fgf8 Het) exhibited a ~50% reduction in GnRH neuron number at birth. Female Fgf8 Het mice were fertile but showed significantly delayed puberty. However, it was unclear if these mice suffered additional loss of GnRH neurons after birth, and if male Fgf8 Het mice had normal pubertal transition and testicular function. In this study, we examined postnatal GnRH neuron number and hypothalamic GnRH content in Fgf8 Het mice from birth to 120 days of age. Further, we examined seminal vesicle and testicular growth, testicular histology, and circulating luteinizing hormone (LH) around and after pubertal transition. Our results showed that GnRH neuron numbers were significantly and consistently reduced in Fgf8 Het mice of both sexes in all ages examined, suggesting these animals were born with an inherently defective GnRH system, and no further postnatal loss of GnRH neurons had occurred. Despite an innately compromised GnRH system, male and female Fgf8 mice exhibited normal levels of immunoassayable hypothalamic GnRH peptide at all ages examined except on 60 days of age, suggesting increased GnRH synthesis or reduced turnover as a compensatory mechanism. Fgf8 Het males also had normal seminal vesicle and testicular mass/body mass ratios, testicular histology, and circulating LH. Overall, our data speak to the extraordinary ability of a GnRH system permanently compromised by developmental defect to overcome pre-existing deficiencies to ensure pubertal progression and reproduction.

No MeSH data available.


Related in: MedlinePlus