Abstract
The Retinoblastoma protein, Rb, was shown to regulate distinct aspects of neurogenesis in the embryonic and adult brain besides its primary role in cell cycle control. It is still unknown, however, whether Rb is required for tissue morphogenesis and the establishment of synaptic connections between adjacent tissues during development. We have investigated here the role of Rb during development of the olfactory system (OS), which heavily relies on reciprocal interactions between the olfactory epithelium (OE) and the olfactory bulb (OB). We show that mice carrying a telencephalic-specific deletion of Rb display several neurogenic defects in the OS during late development. In the OE, loss of Rb leads to ectopic proliferation of late-born progenitors (Tuj-1+), abnormal radial migration and terminal maturation of olfactory sensory neurons (OSNs). In the OB, deletion of Rb causes severe lamination defects with loss of clear boundaries between distinct layers. Importantly, starting around E15.5 when OB glomerulogenesis is initiated, many OSNs axons that project along the olfactory nerve layer (ONL) fail to properly innervate the nascent bulb, thus resulting in partial loss of connectivity between OE-OB and gradual neuronal degeneration in both tissues peaking at birth. This deficiency correlates with deregulated expressions of two key chemo-repellant molecules, Robo2/Slit1 and Nrp2/Sema3F that control the formation of dorsal-ventral topographic map of OSNs connections with OB glomeruli. This study highlights a critical requirement for Rb during neurogenesis and the establishment of proper synaptic connections inside the OS during development.
Highlights
The mammalian olfactory system (OS) is a pseudostratified neuroepithelium comprised of the olfactory epithelium (OE) and the olfactory bulb (OB)
Around E15, when glomerulogenesis begins in the OB, olfactory sensory neurons (OSNs) axons grow deeper and form synapses with the primary dendrites of the main projection neurons in the OB, the mitral cells (MCs), and the tufted cells (TCs) (Treloar et al, 1999, 2010)
Starting around E14.5-E15, when glomerulogenesis begins in the OB, many OSNs axons projecting along the olfactory nerve layer (ONL) fail to properly connect with the OB in Rb−/− mice compared with control littermates as indicated by cresyl-eosin staining
Summary
The mammalian olfactory system (OS) is a pseudostratified neuroepithelium comprised of the olfactory epithelium (OE) and the olfactory bulb (OB). The Retinoblastoma gene, Rb, is a tumor suppressor gene that primarily controls entry into cell cycle at the G1-S phase checkpoint by directly interacting and inhibiting the function of transcription factors required for DNA synthesis mainly the E2F family of transcription factors (reviewed in Sage, 2012; Cheffer et al, 2013) Besides this primary role, recent studies have implicated the Rb/E2F pathway in the control of many aspects of neurogenesis in the brain including neuronal differentiation in the ventral cortex (Ghanem et al, 2012), migration in the dorsal and the ventral cortices (Ferguson et al, 2005; McClellan et al, 2007; Ruzhynsky et al, 2007; Ghanem et al, 2012) and survival in the adult olfactory bulb (Naser et al, 2016). This latter defect correlates with the deregulated expressions of key chemo-repellant molecules that control the formation of the D/V topographic map inside the OS
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