Multipotent Neural Stem Cells Reside into the Rostral Extension and Olfactory Bulb of Adult Rodents

Abstract

The lateral walls of the forebrain lateral ventricles are the richest source of stem cells in the adult mammalian brain. These stem cells give rise to new olfactory neurons that are renewed throughout life. The neurons originate in the subventricular zone (SVZ), migrate within the rostral extension (RE) of the SVZ along the rostral migratory stream (RMS) within tube-like structures formed of glial cells, to eventually reach the olfactory bulb (OB). We demonstrate that, contrary to the current view, multipotential (neuronal-astroglial-oligodendroglial) precursors with stem cell features can be isolated not only from the SVZ but also from the entire RE, including the distal portion within the OB. Specifically, these stem cells do not derive from the migratory neuroblasts coming from the SVZ. Interestingly, stem cells isolated from the proximal RE generate significantly more oligodendrocytes, and those from the distal RE proliferate significantly more slowly than stem cells derived from the SVZ and other RE regions. These findings demonstrate that stem cells are not confined to the forebrain periventricular region and indicate that stem cells endowed with different functional characteristics occur at different levels of the SVZ-RE pathway. Key words: adult neural stem cells; multipotent precursors; forebrain subventricular region; rostral extension; olfactory bulb; neurogenesisMultipotential neural stem cells can be isolated from the forebrain periventricular region of the adult mammalian brain (Reynolds and Weiss, 1992;Richards et al., 1992;Morshead et al., 1994;Gritti et al., 1996;Temple and Alvarez-Buylla, 1999;Doetsch et al., 1999a, Johansson et al., 1999. The subventricular zone (SVZ) lines most of the lateral wall of the lateral ventricles in adult rodents. Although in vitro forebrain periventricular stem cells display multipotency (for review, see Weiss et al., 1996;McKay, 1997;Temple and Alvarez Buylla, 1999;Gage, 2000), in vivo SVZ precursors generate primarily committed neuronal precursors that migrate tangentially along the rostral extension (RE) of the SVZ toward the olfactory bulb (OB), constituting the rostral migratory stream (RMS). Within the RMS these neuroblasts (type A cells) form elongated aggregates called chains and continue to divide while migrating (Menezes et al., 1995;Wichterle et al., 1997) through glial tunnels formed by the processes of astrocytes (type B cells; Lois et al., 1996). After reaching the core of the OB they move radially into the granular and periglomerular layers, where they differentiate into mature neurons (Luskin, 1993;Lois and Alvarez-Buylla, 1994). These findings gave rise to the current view that the forebrain periventricular region is a stem cell reservoir, and the RE is a conduit for the neuronal progeny of these cells that are targeted to more rostral brain regions. This view renders the idea that the RE itself could be a primary source of multipotential stem cells rather counterintuitive. However, it has been observed that the ratio of proliferating to nonprolife...

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