The developmental regulation of phenotypic diversity in the mammalian central nervous system (CNS) was studied using the enkephalin (ENK) phenotype and gene as model at the molecular and cellular level with special emphasis a) on the identification and functional role of cis- elements of the rat enkephalin (rENK) gene and identification and isolation of their trans-factors; b) on the identification of cellular interactions and extracellular signals that regulate phenotypic differentiation. To a): A cDNA encoding for a novel member of Matrix-Attachment-Region (MAR)-binding proteins, BAD- 1 (Brain-, A/T-, Development-specific protein 1), was isolated; Three novel developmentally regulated, lineage-specific, octamer-like proteins (p-sept, n-sept and g-sept) were identified and characterized; following binding to the DNA recognition site, these proteins bend the DNA in a lineage-specific fashion; development- and brain-region-specific splice variants of the lymphoid-specific transcription factor Ikaros were found expressed in the developing brain; the phenotypic fate of differentiating neurons were successfully altered by using DNA molecular decoy; transgenic animals harboring various regions of the ENK gene in a CRE-lox-based targeting system were generated. To b):In the Down-syndrome/Alzheimer's disease model trisomic glia was found responsible for the cholinergic deficit.
