Neural cells derived by in vitro differentiation of P19 and embryonic stem cells.

Abstract

The past decade has seen great progress in understanding the key genes involved in GABAergic transmission. The genes for GAD, multiple subunits of the ionotropic GABA receptors, metabotropic GABA receptors, and GABA uptake proteins have been cloned. Analysis of the cloned genes has yielded a plethora of fundamental insights into the role of the corresponding proteins in mediating GABAergic signals (reviewed in Tobin et al. and Erlander and Tobin). Tools based on these new studies, ranging from monoclonal antibodies to gene probes, have also allowed detailed mapping of expression patterns in the central nervous system (CNS). These new studies reveal that some components of GABAergic transmission have a very wide distribution, being expressed by GABAergic neurons throughout the CNS. Others have a much more restricted pattern of expression. The highly specific expression of GABAergic genes poses a set of fundamental challenges to developmental neurobiology. What genetic mechanisms underlie these patterns of expression? How are complex structures such as receptors assembled? How do the components of a GABAergic synapse come to be localized in proximity to each other so as to make functional transmission possible? Cell lines that express GABAergic phenotypes play an important part in answering these and related questions. With appropriate cell lines it should be possible to manipulate genes related to the GABAergic phenotype in ways that shed light on these questions. Recently, work from several laboratories, including our own, has shown that two pluripotent cell lines from the mouse, the P19 embryonal carcinoma line and embryonic stem (ES) cells, are capable of differentiating into neuron-like cells with GABAergic phenotypes. Since these cell lines are highly suitable for genetic manipulation, they should be extremely useful for studying the relationship between GABA-related genes and the phenotypes they encode.