The role of the retinoblastoma protein (pRb) in the development of the olfactory system -

Abstract

The Retinoblastoma, pRb, is a tumor suppressor gene that plays important roles in brain development primarily by controlling cell division at the G1-S phase checkpoint. In addition, loss of Rb causes neuronal differentiation and migration defects in the developing brain. We investigated here the role of Rb in the development of the olfactory system (OS) which is comprised of the olfactory epithelium (OE) and the olfactory bulb (OB). Neuron formation or neurogenesis and synapse creation or synaptogenesis in the OS are regulated by reciprocal interactions between the OE and the OB during development. We analyzed layer organization inside the OS and studied the development of the olfactory sensory neurons (OSN) and olfactory nerve layer (ONL) in the absence of Rb. To do this, we performed a conditional Rb’s deletion in the telencephalon and OS by crossing Foxg1-Cre mice and Rbfloxed-floxed mice. Then, we analyzed the OS phenotype in Rb-null mice and control littermates between E12.5 and birth using used cresyl-eosin staining, immunohistochemistry and in situ hybridization. We assessed neurogenesis and synaptogenesis in the OS and found that, starting E15.5, loss of Rb leads to: 1) enhanced neurogenesis manifested by increased progenitor proliferation of immature OSNs and thereafter, increased thickness of the mutant OE, 2) aberrant radial migration causing ectopic localization of immature OSNs in the intermediate zone of OE and coupled to terminal maturation defects in OSNs, 3) increased apoptosis in both the OB and OE with gradual degeneration of the latter around birth, and finally, 4) axonal guidance defects affecting the ONL and leading to a loss of connectivity between the OB and OE during late development. Our data demonstrates that Rb is required for normal development and morphogenesis of the OS and emphasizes a novel role for this cell cycle protein in the establishment of appropriate neuronal connections between different brain regions.