Tempting Fate and Commitment in the Developing Forebrain

Transplantation of cells to a new site challenges phenotypic potential, giving cells opportunities to make new choices, and thus revealing those features governed by environmental cues as well as the time frame in which cues influence specific features. One model of tissue differentiation, which postulates a progressive acquisition of a cell's final fate (10xGreenwald, I and Rubin, G.M. Cell. 1992; 68: 271–281Abstract | Full Text PDF | PubMedSee all References, 12xLevitt, P, Ferri, R.T, and Barbe, M.F. Persp. Dev. Neurol. 1993; 1: 65–74PubMedSee all References, 13xMcConnell, S.K. Neuron. 1995; 15: 761–768Abstract | Full Text PDF | PubMed | Scopus (287)See all References), is generally applicable to the current graft findings. In this scheme, the final phenotype of any cell results from the interplay between genetic endowment and the stepwise exposure of the cell to changing environmental cues, such as local cell–cell interactions and afferent input; each step narrows the possible choices within each subsequent step. I have modified the originally proposed model to include the findings of several grafting experiments (Figure 1Figure 1), highlighting how ventricular zone cells may be influenced by local environmental cues that move the population through specific periods of developmental restrictions. The recent studies by Brustle et al. 1995xBrustle, O, Maskos, U, and McKay, R.D.G. Neuron. 1995; 15: 1275–1285Abstract | Full Text PDF | PubMed | Scopus (169)See all ReferencesBrustle et al. 1995 and Campbell et al. 1995xCampbell, K, Shah, N, Rao, M, and Anderson, D.J. Neuron. 1995; 15: 1259–1273Abstract | Full Text PDF | PubMed | Scopus (155)See all ReferencesCampbell et al. 1995 provide additional evidence supporting the above model of development. The grafting studies discussed above, which examine tangential migration, regional identities, and nuclear grouping or laminar identities, reveal that early striatal and cortical proliferating cells are multipotential; the onset of neurogenesis appears to trigger an early commitment of these progenitors to several aspects of areal and nuclear or laminar organization. Local cues that influence these choices must act on the cells prior to their final mitotic phase. Postmitotic migrating cells are also influenced by local cues, although their responsiveness to cues is limited by the choices made by the progenitor before it exits the ventricular zone. The laminar and regional identities chosen prior to migration further limit the connectivity choices the cell is able to make. Late-developing features such as afferent input, selective elimination of exuberant connections, and barrel formation appear to be influenced by activity-dependent signals.Figure 1Developmental Time Line Depicting the Choices a Grafted Cell Might Make as It Undergoes Neurogenesis and HistogenesisNote that striatal cells would make nuclear organizational choices, as opposed to laminar choices.View Large Image | View Hi-Res Image | Download PowerPoint SlideIn summary, grafting paradigms using precursor or postmitotic cells allow the elucidation of the mechanisms of cellular specification. Such experimental manipulation will likely continue to contribute to our understanding of developmental potentials and phenotypic differentiation leading to normal brain function. The studies discussed here, as well as many others, strongly suggest a mechanism by which cells acquire phenotypic traits progressively, influenced most strongly by as yet undefined environmental cues that may be spatially and/or temporally restricted during forebrain development.