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.
Highlights
Neurons that synthesize and secrete gonadotropin-releasing hormone (GnRH) are critical to vertebrate reproduction
Our results show that Fgf8 deficiency obliterates half of Gonadotropin-releasing hormone (GnRH) neuronal population prenatally and permanently in both sexes, but all mice compensate for this innate GnRH system deficit by increasing the levels of the GnRH peptide before, during, and after puberty with only some rare exceptions
When GnRH neuronal count in Fgf8 Het males was analyzed as percent of GnRH neurons found in agematched 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
Summary
Neurons that synthesize and secrete gonadotropin-releasing hormone (GnRH) are critical to vertebrate reproduction. The development of GnRH neurons is orchestrated by a multitude of signaling factors [1,2,3]. The importance of these factors is underscored by observations that loss-of-function mutations in many of these signaling molecules could lead to. Studies in mice confirm that many of the Fgf signaling genes are expressed prominently in the olfactory placode, the birthplace of GnRH neurons [16, 17], and their deficiencies could lead to severely reduced GnRH neuronal population [15, 18,19,20,21,22]. Heterozygous Fgf hypomorphic mice (Fgf Het) exhibit a 50% reduction in GnRH neurons at birth [20], whereas newborn homozygous Fgf hypomorphic mice exhibit a complete elimination of GnRH neurons due to fate specification failure [20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
