title: The Netrin/RGM receptor, Neogenin, controls adult neurogenesis by promoting neuroblast migration and cell cycle exit.
abstract: A comprehensive understanding of adult neurogenesis is essential for the development of effective strategies to enhance endogenous neurogenesis in the damaged brain. Olfactory interneurons arise throughout life from stem cells residing in the subventricular zone of the lateral ventricle. Neural precursors then migrate along the rostral migratory stream (RMS) to the olfactory bulb. To ensure a continuous supply of adult-born interneurons, precursor proliferation, migration, and differentiation must be tightly coordinated. Here, we show that the netrin/repulsive guidance molecule receptor, Neogenin, is a key regulator of adult neurogenesis. Neogenin loss-of-function (Neo(gt/gt)) mice exhibit a specific reduction in adult-born calretinin interneurons in the olfactory granule cell layer. In the absence of Neogenin, neuroblasts fail to migrate into the olfactory bulb and instead accumulate in the RMS. In vitro migration assays confirmed that Neogenin is required for Netrin-1-mediated neuroblast migration and chemoattraction. Unexpectedly, we also identified a novel role for Neogenin as a regulator of the neuroblast cell cycle. We observed that those neuroblasts able to reach the Neo(gt/gt) olfactory bulb failed to undergo terminal differentiation. Cell cycle analysis revealed an increase in the number of S-phase neuroblasts within the Neo(gt/gt) RMS and a significant reduction in the number of neuroblasts exiting the cell cycle, providing an explanation for the loss of mature calretinin interneurons in the granule cell layer. Therefore, Neogenin acts to synchronize neuroblast migration and terminal differentiation through the regulation of neuroblast cell cycle kinetics within the neurogenic microenvironment of the RMS.
authors.affiliation: The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.
authors.forename: Conor J
authors.initials: CJ
authors.lastname: O'Leary
authors.forename: DanaKai
authors.initials: D
authors.lastname: Bradford
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Amanda
authors.initials: A
authors.lastname: White
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Blackmore
authors.forename: Helen M
authors.initials: HM
authors.lastname: Cooper
mesh_terms: D000818:Animals; D064032:Calbindin 2 / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D060833:Cellular Microenvironment; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000075386:Netrin Receptors; D055495:Neurogenesis; D009830:Olfactory Bulb / Q000166:cytology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D016196:S Phase
chemical_list: C576511:Calb2 protein, mouse; D064032:Calbindin 2; D008565:Membrane Proteins; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C091279:neogenin
keywords: Adult stem cells; Cell cycle; Neural differentiation; Neural stem cells; Rostral migratory stream