Foxg1 and Retinoic Acid Signaling Regulate Zonal Patterning in the Developing Olfactory Epithelium

Odor information processing begins in the olfactory epithelium (OE), which in mice is spatially divided into two zones: the dorsomedial zone (D-zone), responsible for innate aversive behaviors, and the ventrolateral zone (V-zone), associated with learning-dependent behaviors. This zonal organization provides the structural framework for olfactory circuit function. However, the mechanisms driving OE zonal specification remain unclear. To investigate the initial segregation of the OE zones, we examined the role of Foxg1, a forkhead transcription factor expressed in the V-zone throughout life. Conditional deletion of Foxg1 in Sox2-expressing OE stem cells, coupled with lineage tracing, revealed ectopic localization of Foxg1-lineage cells in the D-zone, without altering their regional molecular profile. These results demonstrate that Foxg1 is essential for zonal segregation but is dispensable for zone-specific molecular identity. We further revealed retinoic acid (RA) as an upstream morphogen regulating D-zone-specific gene expression. RA signaling is tightly confined to the D-zone, ensuring OE regional identity. These findings suggest that the establishment of D- and V-zones is driven by interactions between morphogenic signal and transcriptional program involving Foxg1, providing a molecular basis for understanding the formation of innate and learned olfactory circuits.