POU Domain Factor Research Articles

Sperm 1: a POU-domain gene transiently expressed immediately before meiosis I in the male germ cell.

Members of the POU-domain gene family encode for transcriptional regulatory molecules that are important for terminal differentiation of several organ systems, including anterior pituitary, sensory neurons, and B lymphocytes. We have identified a POU-domain factor, referred to as sperm 1 (Sprm-1). This factor is most related to the transactivator Oct-3/4, which is expressed in the early embryo, primordial germ cells, and the egg. However, in contrast with Oct-3/4, rat Sprm-1 is selectively expressed during a 36- to 48-hr period immediately preceding meiosis I in male germ cells. Although the POU-domain of Sprm-1 is divergent from the POU-domains of Oct-1 and Oct-2, random-site-selection assay reveals that Sprm-1 preferentially binds to a specific variant of the classic octamer DNA-response element in which the optimal sequence differs from that preferred by Oct-1 and Pit-1. These data suggest that the Sprm-1 gene encodes a DNA-binding protein that may exert a regulatory function in meiotic events that are required for terminal differentiation of the male germ cell.

Brn-5 is a divergent POU domain factor highly expressed in layer IV of the neocortex.

We have identified rat cDNA clones that encode a POU domain protein, referred to as brain-5 (Brn-5). During embryogenesis in the rat, Brn-5 is widely expressed with highest levels in the developing brain and spinal cord from embryonic day 12.5. In the adult, Brn-5 mRNA is most abundant in the brain, where it is diffusely expressed with the exception of an enrichment in layer IV of the neocortex. However, Brn-5 is also found in multiple adult tissues outside the central nervous system, including kidney, lung, heart, adrenal, skin, testis, and anterior pituitary. This expression pattern contrasts with that of most other POU domain genes that are expressed predominantly in the developing nervous system and are progressively restricted to discrete regions of the brain. The predicted amino acid sequence of Brn-5 is considerably divergent from previously described POU domains and thus defines a new POU domain subclass (class VI). Consistent with its divergent sequence, the DNA-binding characteristics of Brn-5 overlap with, but are clearly distinct from, that of Oct-2. Although Brn-5 can bind to non-octamer sites, a random site selection indicates that its preferred binding site contains a variant octamer core motif. Finally, we show that the amino terminus of Brn-5 contains a transactivation domain.

Identification of a novel zinc finger protein binding a conserved element critical for Pit-1-dependent growth hormone gene expression.

The growth hormone (GH) and prolactin genes require the pituitary-specific POU domain transcription factor Pit-1 for their activation. However, additional factors are necessary for the effective expression of these genes. Analysis of evolutionarily conserved sequences in the proximal GH promoter suggests the critical importance of one highly conserved element located between the two Pit-1 response elements. Mutation of this site decreases expression of a transgene in mice > 100-fold. We have identified a major activity binding to this site as a novel member of the Cys/His zinc finger superfamily, referred to as Zn-15. The Zn-15 DNA-binding domain comprises three zinc fingers separated by unusually long linker sequences that would be expected to interrupt specific DNA site recognition. Zn-15 synergizes with Pit-1 to activate the GH promoter in heterologous cell lines in which this promoter is only minimally responsive to Pit-1 alone. Our data suggest that functional interactions between the tissue-specific POU domain factor Pit-1 and this novel zinc finger factor binding to an evolutionarily conserved region in the GH promoter may constitute an important component of the combinatorial code that underlies the effective expression of the GH gene.

A tissue-specific enhancer confers Pit-1-dependent morphogen inducibility and autoregulation on the pit-1 gene.

Pit-1 is a tissue-specific POU domain factor obligatory for the appearance of three cell phenotypes in the anterior pituitary gland. Expression of the pit-1 gene requires the actions of a cell-specific 390-bp enhancer, located 10 kb 5' of the pit-1 transcription initiation site, within sequence that proves essential for effective pituitary targeting of transgene expression during murine development. The enhancer requires the concerted actions of a cell-specific cis-active element, Pit-1 autoregulatory sites, and atypical morphogen response elements. Pituitary ontogeny in the Pit-1-defective Snell dwarf mouse reveals that pit-1 autoregulation is not required for initial activation or continued expression during critical phases of Pit-1 target gene activation but, subsequently, is necessary for maintenance of pit-1 gene expression following birth. A potent 1,25-dihydroxyvitamin D3-responsive enhancer element defines a physiological site in which a single nucleotide alteration in the sequence of core binding motifs modulates the spacing rules for nuclear receptor response elements. Unexpectedly, the major retinoic acid response element is absolutely dependent on Pit-1 for retinoic acid receptor function. On this DNA element, Pit-1 appears to function as a coregulator of the retinoic acid receptor, suggesting an intriguing linkage between a cell-specific transcription factor and the actions of morphogen receptors that is likely to be prototypic of mechanisms by which other cell-specific transcription factors might confer morphogen receptor responsivity during mammalian organogenesis.

POU-domain transcription factors: pou-er-ful developmental regulators.

This paper reviews the characterization of a gene family that contains a novel DNA-binding motif ― the POU domain ― which appears to exert critical developmental actions, providing insights into the mechanisms by which distinct cellular phenotypes emerge during organogenesis. This review will also summarize the known POU-domain factors, the unique features of their interactions with cognate DNA-binding sites, and the recent evidence of their specific developmental and transcriptional functions