Abstract
Fibroblast growth factor 8 (FGF8) is a potent morphogen that regulates the ontogenesis of gonadotropin-releasing hormone (GnRH) neurons, which control the hypothalamus-pituitary-gonadal (HPG) axis, and therefore reproductive success. Indeed, FGF8 and FGFR1 deficiency severely compromises vertebrate reproduction in mice and humans and is associated with Kallmann Syndrome (KS), a congenital disease characterized by hypogonadotropic hypogonadism associated with anosmia. Our laboratory demonstrated that FGF8 signaling through FGFR1, both of which are KS-related genes, is necessary for proper GnRH neuron development in mice and humans. Here, we investigated the possibility that non-genetic factors, such as the epigenome, may contribute to KS onset. For this purpose, we developed an embryonic explant model, utilizing the mouse olfactory placode (OP), the birthplace of GnRH neurons. We show that TET1, which converts 5-methylcytosine residues (5mC) to 5-hydroxymethylated cytosines (5hmC), controls transcription of Fgf8 during GnRH neuron ontogenesis. Through MeDIP and ChIP RT-qPCR we found that TET1 bound to specific CpG islands on the Fgf8 promoter. We found that the temporal expression of Fgf8 correlates with not only TET1 binding, but also with 5hmC enrichment. siRNA knockdown of Tet1 reduced Fgf8 and Fgfr1 mRNA expression. During this time period, Fgf8 also switched histone status, most likely via recruitment of EZH2, a major component of the polycomb repressor complex-2 (PRC2) at E13.5. Together, these studies underscore the significance of epigenetics and chromatin modifications to temporally regulated genes involved in KS.
Highlights
Fibroblast growth factors (FGFs) are well-known signaling proteins that are crucial for neuronal fate specification, progenitor cell proliferation, and cell survival [1,2,3,4,5,6,7]
We show that Fgf8 transcription is temporally regulated via TET1 during development of the gonadotropin-releasing hormone (GnRH) system in the embryonic mouse olfactory placode (OP)
We found that TET1 continued to interact with specific CpG-rich regions on the Fgf8 promoter after emergence of GnRH neurons
Summary
Fibroblast growth factors (FGFs) are well-known signaling proteins that are crucial for neuronal fate specification, progenitor cell proliferation, and cell survival [1,2,3,4,5,6,7]. Our previous studies showed that FGF8 signaling is required for gonadotropin-releasing hormone (GnRH) neuron ontogenesis in the OP [2,3,5,14] It is still not understood what drives Fgf transcription in the developing OP. Several studies showed that multiple downstream, conserved DNA sequences could recapitulate Fgf expression patterns in both zebrafish and mouse embryos [23,24,25]. These studies suggested chromosomal conformation is dynamically regulated in the context of tissue type, and that both activating and repressive cis-regulatory elements can drive Fgf expression. Few studies have addressed the chromatin state of the Fgf locus, which is likely to play a role in cis-regulatory enhancer-promoter interactions, or alternatively, how the epigenomic state may control the temporal regulation of Fgf transcription
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.
