The olfactory bulb (OB) is found in all vertebrates and is the first relay station of the olfactory information in the brain. In the OB, projection neurons, mitral and tufted cells, receive olfactory input from the olfactory sensory neurons and transmit the information to the olfactory cortex. However, some people are born with congenital anosmia/hyposmia associated with dysgenesis of the OB (Koenigkam-Santos et al., 2011; Pinto et al., 2005). Particularly, defect in projection neuron development often results in OB hypoplasia (Hevner et al., 2001; Sessa et al., 2008). Knowledge about the molecular mechanisms regulating the development of OB projection neurons is necessary to understand the formation of olfactory circuits as well as congenital olfactory defects.

In the embryonic brain, mitral cell precursors are generated from OB RGCs, which are radial glial cells (RGCs) located in the presumptive OB (pOB; the anterior tip of the telencephalic vesicle) (Imamura et al., 2011; Imamura and Greer, 2013; Puche and Shipley, 2001). These precursor cells radially migrate within the pOB to form a thin mitral cell layer (MCL) and differentiate into mitral cells (Blanchart et al., 2006; Imamura and Greer, 2013). Each step is regulated by multiple molecules and signaling pathways. Molecular mechanisms regulating RGC development have been well-studied in the cerebral cortex (Agirman et al., 2017; Ferent et al., 2020; Paridaen and Huttner, 2014). Briefly, the proliferation and maintenance of cortical RGCs are regulated by fibroblast growth factors (FGFs), epidermal growth factor (EGF), insulin growth factor (IGF), brain-derived neurotrophic factor (BDNF), bone morphogenic proteins (BMPs), sonic hedgehog (SHH), WNTs, and Notch ligands. Our previous RNA-seq analysis revealed that FGF receptors (FGFRs), BMP receptors (BMPRs), and Notch are strongly expressed in the OB during development (Kawasawa et al., 2016). However, even though mitral cells are often presented as the OB counterpart of cortical pyramidal neurons, it is unclear whether these molecules play the same roles in developing cortex and OB. This is because mitral cells are regulated by unique mechanisms distinct from those of cortical pyramidal neurons; OB RGCs generate OB projection neurons through a mechanism called direct neurogenesis that bypasses the production of intermediate progenitor cells (IPCs), whereas the cortical RGCs follow IPC-mediated indirect neurogenesis to generate pyramidal neurons (Cardenas et al., 2018; Hevner, 2019; Imamura and Greer, 2013).

Mutations in the fgf8 or fgfr1 gene cause a genetic disease called Kallmann syndrome, in which patients exhibit anosmia and lack bilateral OB without major abnormalities in the cerebral cortex (Au et al., 2011). Mimicking this defect, mice having a hypomorphic mutation in fgf8 or mice lacking fgfr1 showed abnormal OB development (Hebert et al., 2003; Storm et al., 2006). Therefore, it has been clearly shown that FGFs are important regulators of the OB projection neuron development, but their roles are not yet fully understood. To examine the role of FGFs in the development of OB projection neurons in detail, we blocked FGF signaling in OB RGCs, which caused OB hypoplasia with disorganized layer formation. Here, we report that FGF signaling inhibition accelerates the neuronal differentiation of OB RGCs and impairs the migration of mitral cell precursors. Furthermore, we report that suppression of BMP signaling by FGF is required for the migration and proper layer formation of mitral cells.