A Novel Family of Cys-Cys, His-Cys Zinc Finger Transcription Factors Expressed in Developing Nervous System and Pituitary Gland

Abstract

A screen designed to identify proteins that specifically bind to retinoic acid response elements resulted in the identification of a rat cDNA encoding a novel protein containing six Cys-Cys, His-Cys zinc fingers. This gene is expressed in a restricted fashion exhibiting distinct temporal and spatial patterns in the developing nervous system, primarily brain, spinal cord, sensory ganglia, retina, and nasal epithelia, as well as in the pituitary, and is referred to as neural zinc finger factor 1 (NZF-1). NZF-1 binds specifically to a cis-regulatory element of the ␤-retinoic acid receptor (RAR␤) gene, as well as to other related DNA elements, including two in the upstream enhancer region of the mouse Pit-1 gene. In heterologous cells, NZF-1 activates transcription from promoters containing specific binding sequences and can synergize with other factors, such as Pit-1, to regulate gene expression. These results suggest that NZF-1 may exert regulatory roles in the developing and mature nervous system and in the pituitary gland. Identification of a second mouse gene highly homologous to NZF-1, encoded by a distinct genomic locus, reveals a dispersed gene family encoding proteins containing Cys-Cys, His-Cys motifs.Precise temporal and spatial patterns of development are controlled by sequential activation of a hierarchy of regulatory genes, which encode transcription factors containing multiple classes of DNA binding motifs. Zinc coordinated fingers are one of the most common DNA binding motifs among eukaryotic transcription factors and are classified based on amino acid sequence of the zinc fingers. The Cys-Cys, His-His class, which is typified by the Xenopus transcription factor IIIA (1), contains the largest number of members. These proteins contain two or more fingers in a tandem repeat. In contrast, steroid receptors, such as the glucocorticoid receptor, contain only two zinc coordinated structures with four (C 4 ) and five (C 5 ) conserved cysteines. The third class of zinc fingers, which also binds to single-stranded nucleic acids, has a consensus sequence of Cys-X 2 -Cys-X 4 -His-X 4 -Cys. Such factors are found in transposable element copia, plants, and mammalian cells as well as in retroviruses. Other metal-coordinating proteins have different structures such as C 6 in the yeast GAL4 protein and a cysteinerich structure in the E1A oncoprotein (2).In accordance with their structural diversity, zinc finger proteins play a variety of important roles in cell growth, differentiation, and development. Transcription factor IIIA and the ubiquitous transcription factor SP1 are broadly involved in the regulation of transcription, whereas the Drosophila zinc finger proteins Krü ppel and Hunchback are crucial for proper segmentation of the developing embryo (3-5). In humans, mutations in a kidney zinc finger protein (WT1) result in Wilm's tumor (6, 7). Recently, a zinc finger protein (REST) has been shown to repress neuronal gene expression in non-neuronal tissues (8, 9).Because retinoic acid receptor (RAR) 1 binds ineff...

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