INDICATOR EXPRESSION DIRECTED BY REGULATORY SEQUENCES OF THE GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP) GENE - IN-VIVO COMPARISON OF DISTINCT GFAP-LACZ TRANSGENES

An increase in the expression of the glial fibrillary acidic protein ( GFAP) gene by astrocytes appears to constitute a crucial component of the brain's response to injury because it is seen in many different sp ecies and features prominently in diverse neurological diseases. Previ ously, we have used a modified GFAP gene (C-339) to target the express ion of beta-galactosidase (beta-gal) to astrocytes in transgenic mice (Mucke et al.; New Biol 3:465-474 1991). To determine to what extent t he in vivo(1) expression of GFAP-driven fusion genes is influenced by intragenic GFAP sequences, the E. coli lacZ reporter gene was either p laced downstream of approximately 2 kb of murine GFAP 5' flanking regi on (C-259) or ligated into exon 1 of the entire murine GFAP gene (C-44 5). Transgenic mice expressing C-259 versus C-445 showed similar level s and distributions of beta-gal activity in their brains. Exclusion of intragenic GFAP sequences from the GFAP-lacZ fusion gene did not dimi nish injury-induced upmodulation of astroglial beta-gal expression or increase beta-gal expression in non-astrocytic brain cells. These resu lts demonstrate that 2 kb of murine GFAP 5' flanking region is suffici ent to restrict transgene expression primarily to astrocytes and to me diate injury-responsiveness in vivo. This sequence therefore constitut es a critical target for mediators of reactive astrocytosis. While acu te penetrating brain injuries induced focal increases in beta-gal expr ession around the lesion sites in C-259, C-445, and C-339 transgenic m ice, infection of C-339 transgenic mice with scrapie led to a widespre ad upmodulation of astroglial beta-gal expression. Hence, GFAP-lacZ tr ansgenic mice can be used to monitor differential patterns of astrogli al activation in vivo. These and related models should facilitate the assessment of strategies aimed at the in vive manipulation of GFAP exp ression and astroglial activation. (C) 1995 Wiley-Liss, Inc.