Figure 1. Model of Cortical Neurogenesis and the Influence of bFGF and Neurotrophins bFGF stimulates division of multipotential stem cells in the cortical VZ. These cells generate restricted neuronal progenitor cells that divide under the influence of mitogens that are as yet uncharacterized. Restricted neuronal progenitor cells become postmitotic and differentiate into cortical neurons. Neurotrophins BDNF and NT-3 may stimulate neuronal differentiation, acting either at the level of the stem cell (A) or at the level of the restricted neuronal progenitor cell (B). bFGF and neurotrophins also act on the postmitotic neuron to stimulate its differentiation and survival (C). Arrowed circle represents cell division. key component of the cell contact effect appears to be membrane associated (Temple and Davis, 1994). Although the identity of this activity is not known, bFGF is a strong candidate. In addition to its known association with extracellular matrix and cell membranes, bFGF is present in the telencephalon as early as E9. 5, and in the cerebral cortex throughout neurogenesis and into adulthood (reviewed in Baird, 1994; Kilpatrick et al., 1995). Addition of bFGF has been shown to stimulate proliferation of cortical neuroectoderm cells in vitro, leading to an increase in neuronal number (Gensburger et al., 1987). More recently, the issue of which type of cortical cell is being stimulated by bFGF has been addressed. In vitro, bFGF has been shown to stimulate cells with characteristics of multipotential stem cells from embryonic telencephalon, E17 cortex, adult hippocampus, and subventricular zone (Gage et al., 1994, Soc. Neurosci., abstract; Kilpatrick et al., 1995). It is not known whether bFGF influences the division of more restricted cortical neuronal progenitor cells, although it does stimulate the division of committed neuronal progenitor cells derived from embryonic striatum (Vescovi et al., 1993) and olfactory epithelium (DeHamer et al., 1994). Is bFGF sufficient to stimulate cortical neuroectoderm cell division by itself? In cases where bFGF has been tested in cultures containing more than one cell, or where cells have been exposed to serum, an interaction between bFGF and other growth factors is possible. For multipotential, highly proliferative cells from embryonic telencepha-Ion, E17 cortex, and adult subventricular zone, the addition of fetal calf serum was required along with bFGF to stimulate division (Kilpatrick and Bartlett, 1993, 1995), suggesting the need for interaction with other factors. In addition, whether bFGF is acting directly as a mitogen in these settings, or whether it is in some way permissive for the mitogenic action of other factors, is not clear. Hence, although we may conclude that there is substantial evidence that bFGF can stimulate division of at least a subset of cortical neuroectoderm cells, the mechanism by which it acts and the role of putative interacting factors remain to be elucidated.

Besides its involvement in neuroectoderm cell proliferation, bFGF has been implicated in neuronal differentiation and survival in the cortex and hippocampus (reviewed in Baird, 1994). Vicario-Abejbn et al.(1995) clearly show that in cultures of E16 hippocampus there is a population of cells that proliferates on administration of bFGF and a population that is stimulated to differentiate. This dual function of bFGF on early phases of division and later phases of differentiation is consistent with the distribution of bFGF and its receptors in both the cortical VZ and the cortical plate (Weise et al., 1993; Baird, 1994).