Spatiotemporal regulation by downstream genes of in the olfactory system: from development to function.

Introduction: Olfaction is important for the quality of life; however, in Kallmann syndrome (KS), defective development results in olfactory dysfunction. Notably, the mechanism underlying olfactory development, especially in the olfactory epithelium (OE), which detects olfactory signals, remains unclear. Mutations in PROK2, which encodes prokineticin-2, have been identified in approximately 9% of the KS patients with olfactory defects.

Methods: We examined olfactory function and analyzed the causes of olfactory dysfunction based on spatiotemporal development and gene expression changes in knockout (KO) model mice with KS.

Results: The ability of the OE to detect olfactory signals was diminished in adult KO mice. Maturation of olfactory sensory neurons (OSNs) in the OE and formation of glomeruli in the olfactory bulb (OB) in adult KO mice were disrupted, thus causing olfactory dysfunction. Furthermore, molecular analysis of KO mice during embryonic development revealed abnormal development of OB layers and diminished differentiation to mature OSNs in the OE at the later stage, which caused defects in the entire olfactory system. Remarkably, downstream signaling genes of , including intermediate filament genes and genes expressed in the putative OB, were found to mediate olfactory system organization.

Discussion: Overall, these findings reveal the role of in olfactory system organization and elucidate how olfactory development defects translate to olfactory function.