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NRL, a bZIP transcription factor of the Maf subfamily, interacts with the homeodomain protein CRX and synergistically regulates rhodopsin expression. Here we report that six isoforms of NRL (29 -35 kDa) are generated by phosphorylation and expressed specifically in the mammalian retina. The anti-NRL antibody also crossreacts with a cytosolic 45-kDa protein, which is detected in neuronal tissues but is not encoded by the NRL gene. In both human retinal cell cultures and sections of fetal and adult human retina, NRL is present in the nuclei of developing and mature rods but not cones. We propose that NRL regulates rod photoreceptor-specific gene expression and is involved in rod differentiation.Retinal photoreceptors are highly specialized neurons that capture photons and convert them to chemical signals. Humans and Old World primates have four distinct photoreceptor types, each with a specific visual pigment (1) and a characteristic retinal distribution (2). Rhodopsin is the photopigment in rod photoreceptors, which dominate primate retina. Rhodopsin provides high sensitivity, but the rod synaptic circuitry yields low spatial resolution. The red, green, and blue visual pigments define the three cone types, whose neural circuits mediate color vision and high spatial resolution but require bright light.Extensive anatomical, lineage, and birth dating studies have demonstrated that the genesis of specific photoreceptor types from retinal progenitors is guided by intrinsic genetic programs, inductive cell-cell interactions, and extrinsic factors (3-6). Postmitotic neurons committed to a photoreceptor cell fate exhibit varying delays before expressing their cell typespecific photopigment, suggesting that the specification of a differentiated rod or cone phenotype requires additional cues (7-10). It is envisaged that these inductive cues turn on a "molecular switch," which leads to expression of a specific visual pigment and other components of the transduction machinery.Cell type-specific gene expression is achieved by combinatorial and synergistic actions of specific activator proteins that recruit the basal transcription machinery to the promoter region (11, 12). Several transcription factor genes are expressed in retina (13-17), and a number of cis-regulatory elements have been identified in retinal gene promoters (18 -20). However, only two transcription factors, NRL and CRX, have so far been implicated directly in modulating photoreceptor-specific gene expression. NRL was isolated from a subtracted human retinal cDNA library and encodes a basic motif-leucine zipper (bZIP) protein (21). It displays strong homology to Maf proteins, which are involved in differentiation and gene regulation (22). NRL was the first transcription factor shown to bind to a cis-regulatory sequence (called NRE or NRL response element) in the rhodopsin promoter and transactivate its activity in cultured cells (23,24). CRX is a photoreceptor-and pineal-specific homeodomain protein that appears to modulate several retinal gene promoters (25-2...

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