Transcriptomic profiling of murine GnRH neurons reveals developmental trajectories linked to human reproduction

Abstract Gonadotropin-releasing hormone (GnRH) neurons play a crucial role in human reproduction and are associated with a spectrum of conditions. However, the underlying biological mechanisms remain elusive due to their small number and sparse distribution. We performed transcriptomic profiling of GnRH neurons during mouse embryonic development, revealing their molecular identity and gene expression dynamics. Our findings show that GnRH neurons undergo a profound transcriptional shift as they migrate from the nose to the brain and that distinct expression trajectories are associated with critical biological processes, including cell migration, neuronal projections, and synapse formation. Cell-to-cell communication analysis revealed timely and spatially restricted modulation of signaling pathways involving known molecules, such as Semaphorins and Plexins, and novel candidates, such as Neurexins and Endothelins. Using GWAS genes linked to human reproductive onset, we found a specific association with GnRH neuron trajectories rising in late developmental stages and involved in neuron maturation and connectivity. Finally, analysis of the genetic burden in a large cohort of patients with congenital GnRH deficiency revealed specific GnRH neuron trajectories with a significant mutation load compared to controls. In conclusion, this study revealed the gene expression dynamics underlying GnRH neuron embryonic development and provides novel insights linking GnRH neuron biology to human reproduction.