Differential regulation of genes encoding synaptic proteins by members of the Brn-3 subfamily of POU transcription factors

Morris, Peter J.; Lakin, Nick D.; Dawson, Sally J.; Ryabinin, Andrey E.; Kilimann, Manfred W.; Wilson, Michael C.; Latchman, David S.

doi:10.1016/s0169-328x(96)00207-0

Cited by 29 publications

(25 citation statements)

References 30 publications

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“…Thus, Brn-3a can directly activate the promoters of genes that are associated with protection against apoptosis (Bcl-2 and Bcl-X L ) and differentiation (e.g. in structural genes such as ␣-internexin (13), neurofilament (9), receptors such as neurotrophin receptor TrkA (14), and synaptic genes such as SNAP-25 (15) and synaptophysin (16)). In addition to direct effects, Brn-3a can also modify gene transcription indirectly by interaction with cellular proteins such as p53, thus effectively increasing the range of target genes regulated by this transcription factor.…”

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Brn-3a Transcription Factor Blocks p53-mediated Activation of Proapoptotic Target Genes Noxa and Bax in Vitro and in Vivo to Determine Cell Fate

Hudson¹,

Morris²,

Latchman

et al. 2005

Journal of Biological Chemistry

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The Brn-3a POU transcription factor is associated with survival and the differentiation of sensory neuronal cells during development. Brn-3a mediates its effects either by the direct regulation of target genes or indirectly upon interaction with proteins such as p53. Brn-3a differentially regulates p53-mediated gene expression and modifies its effect on cell fate. Here we show that, like Bax, Brn-3a antagonizes p53-mediated transcription of another proapoptotic target, Noxa, significantly reducing transactivation of the Noxa promoter by p53. This effect requires the p53 binding site, and electrophoretic mobility shift assay studies suggest that Brn-3a is associated with p53 when it is bound to its site in the Noxa promoter. The wild type but not the mutant promoter can be immunoprecipitated with Brn-3a in chromatin immunoprecipitation assays. Thus, Brn-3a may act by preventing the recruitment of cofactors required for p53 to transactivate this promoter. The co-expression of Brn-3a and p53 results in decreased endogenous Noxa protein in the neuronal cell line, ND7, suggesting a direct functional effect of this interaction. Moreover, there is a significant elevation of both proapoptotic Bax and Noxa proteins in sensory neuronal tissue taken from Brn-3a؊/؊ embryos during development, compared with wild type controls. Striking changes occurred at embryonic day 14.5, a time that precedes a significant loss of specific neurons in the mutant embryos, but not at embryonic day 16.5 when Brn-3a-expressing cells are already lost by apoptosis. Therefore, the lack of antagonism by Brn-3a on activation of proapoptotic p53 target genes may contribute to the increased apoptosis seen in the Brn-3a؊/؊ embryos. These results support a crucial role for Brn-3a in determining the pathway taken by p53 when co-expressed during development and thus in controlling the fate of these cells.During neuronal development, transcription factors, which are expressed in a temporal/spatial manner or in response to specific signals, play a critical role in determining the fate of specific progenitor cells in terms of proliferation, survival and differentiation, or apoptosis of excess cells. This role is necessary to achieve the correct balance of specific neurons required for the normal innervation and function. The pit-1, oct-1/2, and unc-86 (POU) transcription factor Brn-3a protein (also referred to as POU4f1 and Brn-3.0) is essential for the survival and differentiation of specific populations of sensory neuronal cells (1, 2), but the mechanism by which this is achieved has yet to be elucidated fully.Brn-3a is expressed in regions of the developing and adult central nervous system and peripheral nervous system (3, 4). During development, Brn-3a expression is initiated just before neurons exit the cell cycle in the peripheral nervous system and just after exiting the cell cycle in the central nervous system (5). This transcription factor is expressed in and acts as a marker of the earliest postmitotic sensory neurons to appear in primary cultures...

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Brn-3a Transcription Factor Blocks p53-mediated Activation of Proapoptotic Target Genes Noxa and Bax in Vitro and in Vivo to Determine Cell Fate

Hudson¹,

Morris²,

Latchman

et al. 2005

Journal of Biological Chemistry

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“…By regulating genes involved in neurite outgrowth and in the control of cellular death, it represents a key factor in the development and survival of postmitotic sensory neurons (He et al, 1989;Lillycrop et al, 1992;Gerrero et al, 1993;Ninkina et al, 1993). The C-terminal of Brn-3a is necessary and sufficient to regulate promoters such as P21, Synapsin and Synaptophysin (Lakin et al, 1995;Morris et al, 1996), but the transactivation of genes such as Bcl-2 requires the N-terminal activation domain (Smith et al, 1998a, b). Since Bcl-2 is activated by Brn-3a only in neuronal cells it has been speculated that a neuronspecific factor(s) binding to the N-terminal of Brn-3a could be involved in its effects.…”

Section: Discussionmentioning

confidence: 99%

“…Brn-3a contains two activation domains: the POU domain in its carboxy-terminal, (which is also the DNA-binding domain and is common to both forms), and an Nterminal activation domain which is characteristic of the long form of Brn-3a. The isolated POU domain is necessary and sufficient to modulate the transcription of genes such as snap-25, synapsin, synaptophysin and P21 (Lakin et al, 1995;Morris et al, 1996). In contrast, it has been clearly demonstrated that other genes such as Bcl-2 and a-internexin are activated only by the long form of Brn-3a, thus requiring the 84 amino acids of its N-terminal domain as well as the POU domain which mediates the binding to DNA (Smith et al, 1998a).…”

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Functional interaction between the small GTP-binding protein Rin and the N-terminal of Brn-3a transcription factor

Calissano

Latchman

2003

Oncogene

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Brn-3a is a transcription factor belonging to the class IV of POU domain transcription factors. It is expressed throughout the peripheral nervous system but especially in postmitotic sensory neurons of dorsal root ganglia. Brn-3a is known to regulate different genes involved in neuronal differentiation and survival. It has been shown that some of these genes require the N-terminal domain of Brn-3a in order to be activated and this effect is observed only in neurons suggesting that it may require a neuronal-specific cofactor. In order to identify this putative factor(s) we screened a cDNA library via a variant of the original yeast two-hybrid system. By using the N-terminal of Brn-3a as the bait, we have repeatedly isolated a protein named Rin, an incompletely characterized small GTP-binding protein expressed only in neurons. In this work, we describe the evidence for a functional interaction between Brn-3a and Rin and demonstrate the role of Rin in modulating the activation of the Brn-3a regulated egr-1 promoter by the N-terminal domain of Brn-3a.

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“…Thus it has previously been shown that the Brn-3a factor can activate a wide variety of target genes expressed in neuronal cells including those encoding pro-opiomelanocortin (11), the neuronal intermediate filament ␣-internexin (17), and the synaptic vesicle protein 19). In contrast Brn-3b represses the promoters of the ␣-internexin and the gene encoding SNAP-25 and also interferes with their activation by 19), although it can stimulate the promoter of the neuronal nicotinic acetylcholine receptor ␣2 subunit gene which is not affected by .To analyze the functional effects of the Brn-3 factors in more detail, we have used the ND7 neuronal cell line which was generated by the fusion of a mouse neuroblastoma cell line and primary rat dorsal root ganglion neurons (21). We have previously shown (12,22) that when these cells are induced to differentiate to a non-dividing phenotype bearing numerous neurite processes (23), the levels of Brn-3a rise dramatically from a low level in the proliferating cells to a much higher level in the non-dividing cells.…”

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Coordinate Induction of the Three Neurofilament Genes by the Brn-3a Transcription Factor

Smith

Morris

Dawson

et al. 1997

Journal of Biological Chemistry

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The POU domain transcription factor Brn-3a is able to stimulate neurite outgrowth when overexpressed in the neuronal ND7 cell line, whereas the closely related Brn-3b factor does not have this effect. We show that Brn-3a overexpression also enhances the expression of the three neurofilament genes at both the mRNA and protein levels, whereas Brn-3b overexpression has no effect. In addition Brn-3a activates the three neurofilament gene promoters in co-transfection assays in both neuronal and non-neuronal cells. As observed for enhanced neurite outgrowth, the stimulation of neurofilament gene expression and activation of the neurofilament gene promoters is observed with the isolated POU domain of Brn-3a. A single amino acid change in the POU homeodomain of Brn-3a to the equivalent amino acid in Brn-3b abolishes its ability to activate the neurofilament promoters, whereas the reciprocal change converts Brn-3b to an activator of these promoters.The POU (Pit-Oct-Unc) family of transcription factors (for reviews see Refs. 1 and 2) was originally defined on the basis of a common 150 -160-amino acid DNA binding domain held in common between the mammalian transcription factors Pit-1, Oct-1, and Oct-2 and the regulatory protein Unc-86 which plays a key role in the development of neuronal cell types, particularly sensory neurons in the nematode (3, 4). A number of subsequent studies (see for example Ref. 5) have defined a large number of other POU family transcription factors in a variety of organisms that have been classified into subgroups according to their relationships to one another (for review see Ref.2). Among the mammalian POU factors identified in this way, the Brn-3 factors show the closest homology to the nematode protein Unc-86 and together with the Drosophila factors I-POU and tI-POU (6, 7) these factors constitute the POU IV subfamily within the POU family (2). Indeed it has been proposed (8) that the Brn-3 factors constitute the mammalian homologues of .Unlike the situation in the nematode, however, three distinct Brn-3 factors have been identified in mammals that show close homology in the DNA binding POU domain but are considerably less homologous outside it and are encoded by three different genes (9, 10). These factors are Brn-3a (also known as Brn-3 or Brn-3.0) (5, 11, 12), Brn-3b (also known as Brn-3.2) (12, 13), and Brn-3c (also known as Brn-3.1) (11,14). Each of these three factors is expressed in distinct but overlapping sets of neurons in the developing and adult nervous system (5, 11, 13-15) with Brn-3a for example defining the earliest postmitotic neurons to appear in the developing central nervous system (15). This suggests that, like Unc-86, the mammalian Brn-3 factors may play a critical role in the development of specific neuronal cells within the nervous system with each factor having distinct but possibly related roles. In agreement with this, recent experiments (8, 16) have shown that inactivation of the Brn-3b gene results in considerable loss of retinal neurons, whereas mice in which the...

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Differential regulation of genes encoding synaptic proteins by members of the Brn-3 subfamily of POU transcription factors

Cited by 29 publications

References 30 publications

Brn-3a Transcription Factor Blocks p53-mediated Activation of Proapoptotic Target Genes Noxa and Bax in Vitro and in Vivo to Determine Cell Fate

Brn-3a Transcription Factor Blocks p53-mediated Activation of Proapoptotic Target Genes Noxa and Bax in Vitro and in Vivo to Determine Cell Fate

Functional interaction between the small GTP-binding protein Rin and the N-terminal of Brn-3a transcription factor

Coordinate Induction of the Three Neurofilament Genes by the Brn-3a Transcription Factor

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