Elizabeth Grove, Ph.D.

Mechanisms Underlying Control of Cell Fate and Differentiation in Mammalian CNS.

Research Summary

How biological pattern is generated in the vertebrate body and brain is a focus of an intense current research effort. Yet the development of perhaps the most intriguing and complex part of the brain, the cerebral cortex, remains mysterious. Our goal is to identify mechanisms that control pattern formation and cell diversity in the mammalian cortex. We employ techniques of molecular biology, retroviral gene transfer, tissue culture, and neuroanatomy, and are focused at present on two projects:

1. The cerebral cortex is divided into many areas that are anatomically distinct and functionally specialized. How is the developing cortex patterned into different areas, and how do individual neurons develop appropriate, area-specific features? The hippocampus is an attractive model system in which to investigate cortical patterning, partly because it is divided into only four areas, or CA 'fields'. Moreover, we have found that a slice through embryonic hippocampus - containing all the future CA fields - continues to develop in culture. Thus, we can monitor and manipulate patterning as it happens in vitro - directly testing the patterning role of specific cellular and molecular cues. In ongoing studies, we ask what makes newborn cells adopt the distinctive features of a particular CA field; when patterning signals act; where these signals originate (inside or outside the hippocampus), and what is the molecular basis of the signals.
2. A more basic question than how neurons take on a distinctive identity is how cells decide to become neural cells - neurons or glia - at all. Cells make this choice when neural epithelium separates from non-neural epithelium to form the neural tube. However, some cells may remake this decision much later in development: neural epithelium in the medial wall of the embryonic cerebral hemisphere generates not only the hippocampus, but also the non-neural epithelium of the choroid plexus. How is a boundary set up between these two developing tissue districts? And what signals direct cells on either side of the boundary to adopt different fates? We are currently investigating the roles played in these signaling events by members of theWnt gene family and associated developmental control genes.

Selected Papers

Grove EA, Tole S, Limon J, Yip L-w and Ragsdale CW. (1998). The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice. Development 125: 2315-2325.

Lee SM, Tole S, Grove EA and McMahon AP. (2000). A local Wnt3a signal is required for development of the mammalian hippocampus. Development 127: 457-467.

Fukuchi-Shimogori T and Grove EA. (2001). Neocortex patterning by the secreted signaling molecule FGF8. Science 294:1071-1074.

Lu M, Grove EA and Miller RJ. (2002). Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci U S A. 99:7090-5.

Grove EA and Fukuchi-Shimogori T. (2003). Generating the Cerebral Cortical Area Map. Ann. Rev. Neurosci..

Fukuchi-Shimogori T and Grove EA. (In Press and Online) Emx2 patterns the neocortex by regulating FGF positional signaling. Nature Neurosci.