ELEMENTS IN THE 5'-FLANKING SEQUENCES OF THE MOUSE LOW-AFFINITY NGF RECEPTOR GENE DIRECT APPROPRIATE CNS, BUT NOT PNS, EXPRESSION IN TRANSGENIC MICE

We have initiated a characterization of the cis-acting regulatory elem ents of the murine low-affinity NGF receptor (p75(NGFR)) gene. Despite studies in cultured cells that suggest the p75(NGFR) promoter is cons titutive, a detailed analysis of this promoter in five lines of transg enic mice demonstrated a high degree of cell-type specificity: 8.4 kb of 5' flanking sequence directs expression of a lacZ reporter to retin al and CNS neurons normally expressing p75(NGFR). A transgene with 470 bp of 5' flanking sequence is also expressed in the CNS, but its regu lation is aberrant, with a loss of basal forebrain expression, In non- neural tissues, both transgenes were expressed only in the testis, kid ney, anterior pituitary, and pancreatic islets; with the exception of the renal pattern of expression, transgene activity was confined to ap propriate cells within these tissues. In contrast, although expression of both transgenes was prominent in adrenal medulla and gastrointesti nal myenteric neurons, neither construct was active in several sensory or sympathetic ganglia that strongly express the endogenous p75(NGFR) gene, indicating that genetic elements necessary for expression in th ese neurons are not present in these promoter sequences. In addition, neither transgene was activated in Schwann cells during Wallerian dege neration of sciatic nerve. We conclude that regulation df the p75(NGFR ) gene is complex, with the first 470 bp of 5' flanking sequence suffi cient for expression in enteric and CNS neurons and additional element s within the first 8.4 kb of 5' flanking sequence required for restric tion to appropriate CNS neurons, Further regulatory elements are possi bly required for expression in at least some sensory and sympathetic n eurons in the PNS and in Schwann cells. To identify potential regulato ry elements in the 470 bp of 5' flanking sequence from the smaller tra nsgene, we compared the sequences of equivalent regions from the mouse , rat, and human p75(NGFR) genes. This ''phylogenetic footprint'' iden tified conserved motifs potentially important for the regulation of th is gene in the CNS.