Goofy/123Cre Lineage Tracing Differentiates Olfactory and Vomeronasal Neurons from GnRH-1 and Terminal Nerve Neurons During Neuronal Migration and Reveals Additional Olfactory Placode-Derived Cells in the Brain

Abstract The olfactory placode (OP) gives rise to a wide array of chemosensory neurons in the nasal region, including olfactory sensory neurons, vomeronasal sensory neurons, and those of the septal organ and Grueneberg ganglion. During placodal invagination, the OP also produces migratory neurons, including gonadotropin-releasing hormone-1 (GnRH-1) neurons, somatostatin-expressing neurons, Prokineticin Receptor 2 (Prokr2) pioneer/terminal nerve (TN) neurons, which are thought to initiate olfactory bulb development. Despite decades of research, the genetic lineage and molecular identity of OP-derived neuronal types remain under investigation. GnRH-1 neurons play essential roles in reproduction and chemodetection but appear genetically distinct from olfactory and vomeronasal chemosensory neurons. The Golgi-associated olfactory signaling regulator Goofy/Gfy is broadly expressed across the placode-derived nasal chemosensory neurons. To determine whether its expression is specific to nasal chemosensory neurons or it is a shared genetic feature across OP derivatives we characterized Gfy expression and lineage at embryonic and postnatal stages. Our results confirm broad Gfy expression in developing chemosensory neurons and subsets of olfactory pioneer/TN neurons. However, we found that while Gfy was not expressed in GnRH-1 neurons while migrating, analysis at late development and postnatal stages, revealed the existence of Gfy-traced neuronal populations in the basal forebrain, some of which also express GnRH. These findings uncover previously unrecognized genetic heterogeneity among migratory nasal neurons and reinforce previous studies suggesting the existence of additional neurons with nasal origin in the brain. In addition to this, analysis of Gfy expression along the developmental trajectory of vomeronasal sensory neurons at postnatal stages revealed intriguing differences in the developmental dynamics across the two main types of vomeronasal sensory neurons. Competing Interest Statement The authors have declared no competing interest. Footnotes We performed new analyses, which led to different conclusions. Figures and text have been extensively revised.