The appropriate control of proliferation of neural precursors has fundamental implications for the development of the central nervous system and for cell homeostasis/replacement within specific brain regions

Soon after birth, neurogenesis is completed within most brain regions. Notable exceptions are found within germinative areas that persist in restricted CNS regions into adulthood. These include the dentate gyrus of the hippocampus and, particularly, an extensive forebrain periventricular region (PVR) (for reviews, see Peretto et al., 1999; Temple and Alvarez-Buylla, 1999; Gage, 2000; Alvarez-Buylla et al., 2001), which contains multipotent precursors that generate both neurons and glia. In rodents, type-B subventricular progenitors from this region, which are immunoreactive for glial fibrillary acidic protein (GFAP), give rise to neuroblasts and glial cells in vivo (Doetsch et al., 1999). The latter form tube-like scaffolding through which chains of neuroblasts migrate rostrally to reach the olfactory bulb, where they give rise to olfactory bulb interneurons (granule and periglomerular GABAergic cells) (Wichterle et al., 1997). Some type B subventricular (Doetsch et al., 1999) cells and cells derived from the ventricular ependymal layer (Johansson et al., 1999) display stem cell properties, including self-maintenance and multipotentiality (the ability to generate the three major CNS lineages, i.e., neurons, astrocytes and oligodendrocytes). Since their initial isolation (Reynolds and Weiss, 1992), several extra-cellular signals have been identified that regulate proliferation and differentiation of adult neural stem cells (ANSCs). Epidermal growth factor (EGF) (Craig et al., 1996; Gritti et al., 1995; Gritti et al., 1996; Gritti et al., 1999), type2 fibroblast growth factor (FGF2) (Gritti et al., 1995; Gritti et al., 1996; Gritti et al., 1999) and α-transforming growth-factor (TGFα) (Weickert and Blum, 1995; Tropepe et al., 1997) can function as mitogens, both in vivo and in vitro, while ciliary neurotrophic factor (CNTF) (Johe et al., 1996), platelet derived growth factor (PDGF) (Johe et al., 1996), bone morphogenetic protein 2 (BMP2) (Gross et al., 1996) and brain derived neurotrophic factor (BDNF) (Benoit et al., 2001) have been implicated in fate selection and differentiation of NSC progeny (for a review, see McKay, 1997). During telencephalic development, several genes have been identified that regulate specification, proliferation and differentiation of progenitors in the dentate gyrus and olfactory bulbs (Bulfone et al., 1998; Wilson and Rubenstein, 2000; Pleasure et al., 2000; Galceran et al., 2000). Notably, the analysis of Hes1 knocked-out animals during CNS development has revealed that this gene might regulate the proliferation and commitment toward the neuronal lineage of embryonic precursors (Nakamura et al., 2000). Also, loss of 1633 Development 129, 1633-1644 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV1768