Alternative titles; symbols
HGNC Approved Gene Symbol: POU4F2
Cytogenetic location: 4q31.22 Genomic coordinates (GRCh38): 4:146,638,893-146,642,474 (from NCBI)
POU4F2 is a member of the POU-domain family of transcription factors. POU-domain proteins have been observed to play important roles in control of cell identity in several systems. A class IV POU-domain protein, POU4F2 is found in human retina exclusively within a subpopulation of ganglion cells where it may play a role in determining or maintaining the identities of a small subset of visual system neurons.
Xiang et al. (1993) cloned human cDNAs and genomic DNAs encoding BRN3B. The BRN3B gene encodes a 410-amino acid polypeptide that contains several identifiable motifs, including a glycine/serine-rich domain, a histidine-rich domain, and a POU domain. RNA slot blots showed that BRN3B is expressed predominantly in the retina. Immunocytochemistry indicated that the protein is present in the nuclei of a subset of retinal ganglion cells (RGCs), consistent with its role as a transcription factor.
Xiang et al. (1995) showed that BRN3B has 2 closely related homologs, termed BRN3A (601632) and BRN3C (602460). The 3 genes share intron/exon structures but map to distinct chromosomes. Xiang et al. (1995) analyzed the expression patterns of brn3a, brn3b, and brn3c in fetal and adult mouse retina and brain. Antibodies to brn3b identify a large fraction of retinal ganglion cells. The authors found that these 3 transcription factors identify overlapping subsets of retinal ganglion cells and of neurons in the dorsal root and trigeminal ganglia, suggesting that primary somatosensory neurons and retinal ganglion cells share genetic regulatory hierarchies.
Liu et al. (1996) noted that Brn3a and Brn3b are alternatively spliced to produce 2 distinct mRNAs encoding long and short isoforms that differ at their N termini. Using PCR analysis, the authors showed that the relative levels of the 2 variants of Brn3a and Brn3b were regulated to produce different proportions of transcripts in different rat neuronal tissues, as well as in cultured primary and immortalized rat neuronal cells. Similarly, the ratio of these variants was modulated by specific stimuli in a rat neuronal cell line and rat primary neurons.
Xiang et al. (1993) determined that BRN3B contains 2 exons spanning approximately 4 kb of genomic DNA. Southern blotting revealed the presence of at least 3 BRN3B-related genes in humans.
Xiang et al. (1993) used an 800-bp cDNA insert for Southern blot analysis of a panel of 31 HindIII-digested DNAs from human-mouse somatic cell hybrids. The BRN3B gene segregated concordantly with chromosome 4. Xiang et al. (1993) mapped the BRN3B gene to 4q31.2 by fluorescence in situ hybridization.
Smith et al. (1997) reported that the induced differentiation of the ND7 neuronal cell line into nondividing cells bearing neurites is accompanied by a dramatic increase in the level of BRN3A and a corresponding decrease in the level of BRN3B. They found that overexpression of BRN3B reduces process outgrowth and prevents the normal differentiation response. This inhibitory effect is abolished by mutating a single amino acid in the POU homeodomain of BRN3B to its equivalent in BRN3A. Smith et al. (1997) found that the converse mutation in BRN3A allows it to inhibit process outgrowth in response to induction of differentiation.
Wagner et al. (2002) found evidence that disruption of the Wilms tumor-1 gene (WT1; 607102) in mice reduces expression of Pou4f2 and leads to retinal abnormalities. Pou4f2 immunoreactivity was detected in the developing ganglion cell layer of normal embryonic mice, but not in the retina of Wt1-null embryos where the neuroretinas were markedly thinner and contained significantly fewer cells. By RT-PCR, Wagner et al. (2002) found that the Wt1-null mutation specifically affected the mRNA level of Pou4f2 but not that of other POU-domain members. They verified direct and specific activation of POU4F2 by Wt1 by the transfection of Wt1 into human embryonic kidney cells, where expression of Wt1 caused an 8-fold increase in POU4F2 mRNA levels.
Irshad et al. (2004) found that BRN3B overexpression increased the growth rate and invasiveness of IMR-32 human neuroblastoma cells, whereas decreased BRN3B expression lowered these parameters. The enhanced growth of IMR-32 cells induced by BRN3B overexpression was anchorage independent and insensitive to the growth inhibitor retinoic acid. Similarly, high levels of Brn3b enhanced tumor growth in mice in vivo, whereas decreased Brn3b levels slowed tumor growth.
Using transcriptome analysis, Sajgo et al. (2017) showed that Brn3b and Brn3a controlled only small subsets of transcripts in mouse RGC populations. The authors identified extensive combinatorial sets of RGC transcription factors, cell surface molecules, and determinants of neuronal morphology that were differentially expressed in specific RGC populations and selectively regulated by Brn3a and/or Brn3b. Some of these genes intrinsically induced arbor-like processes in epithelial cells, suggesting cell-autonomous neuronal arbor formation mechanisms.
Using alkaline phosphatase staining, Badea et al. (2009) showed that populations of Brn3a- and Brn3b-expressing RGCs had overlapping but distinct distributions of dendritic stratification in mice. Deletion of Brn3a led to an increase in the ratio of bistratified to monostratified RGCs, with only modest RGC loss and little effect on central projections. In contrast, deletion of Brn3b led to greater RGC loss, disorganization of axonal structure in eye and brain, and differential loss and/or dysfunction of central projections, resulting in visual-driven behavioral deficits in mutant mice.
Maskell et al. (2017) found that Brn3a repressed Brn3b in cardiomyocytes of mice by reducing Brn3b promoter activity. Knockout of Brn3a upregulated Brn3b expression, which increased expression of the Brn3b target genes cyclin D1 (CCND1; 168461) and Bax (600040), resulting in cardiomyocyte apoptosis and heart morphologic defects that likely caused death of Brn3a -/- mice soon after birth. Brn3a -/- and Brn3b -/- double-knockout mice suffered early embryonic lethality, indicating the essential and partially overlapping roles of these genes during early embryogenesis. The authors also found that brn3a and brn3b were expressed during zebrafish heart development, and that knockdown of brn3a and brn3b in zebrafish embryos resulted in cardiac defects.
Mele et al. (2019) found that treatment with angiotensin II (ANGII; 106150) induced hypertrophic responses in mouse heart and stimulated Brn3b expression in cardiomyocytes by activating the Brn3b promoter through hypertrophic signaling pathways. Brn3b expression in response to AngII further triggered time-dependent, differential regulation of distinct Brn3b target genes in cardiomyocytes. Hearts from male Brn3b -/- mice had altered contractile efficiency at baseline and reduced hypertrophic responses following AngII treatment. The reduced cardiac function in response to AngII treatment correlated with increased fibrosis and adverse remodeling in Brn3b -/- hearts, suggesting that mutant hearts were unable to adapt to stress.
Badea, T. C., Cahill, H., Ecker, J., Hattar, S., Nathans, J. Distinct roles of transcription factors Brn3a and Brn3b in controlling the development, morphology, and function of retinal ganglion cells. Neuron 61: 852-864, 2009. [PubMed: 19323995] [Full Text: https://doi.org/10.1016/j.neuron.2009.01.020]
Irshad, S., Pedley, R. B., Anderson, J., Latchman, D. S., Budhram-Mahadeo, V. The Brn-3b transcription factor regulates the growth, behavior, and invasiveness of human neuroblastoma cells in vitro and in vivo. J. Biol. Chem. 279: 21617-21627, 2004. Note: Erratum: J. Biol. Chem. 290: 888 only, 2015. [PubMed: 14970234] [Full Text: https://doi.org/10.1074/jbc.M312506200]
Liu, Y. Z., Dawson, S. J., Latchman, D. S. Alternative splicing of the Brn-3a and Brn-3b transcription factor RNAs is regulated in neuronal cells. J. Molec. Neurosci. 7: 77-85, 1996. [PubMed: 8835784] [Full Text: https://doi.org/10.1007/BF02736850]
Maskell, L. J., Qamar, K., Babakr, A. A., Hawkins, T. A., Heads, R. J., Budhram-Machadeo, V. S. Essential but partially redundant roles for POU4F1/Brn-3a and POU4F2/Brn-3b transcription factors in the developing heart. Cell Death Dis. 8: e2861, 2017. Note: Electronic Article. [PubMed: 28594399] [Full Text: https://doi.org/10.1038/cddis.2017.185]
Mele, L., Maskell, L. J., Stuckey, D. J., Clark, J. E., Heads, R. J., Budhram-Mahadeo, V. S. The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart. Cell Death Dis. 10: 621, 2019. Note: Electronic Article. [PubMed: 31413277] [Full Text: https://doi.org/10.1038/s41419-019-1848-y]
Sajgo, S., Ghinia, M. G., Brooks, M., Kretschumer, F., Chuang, K., Hiriyanna, S., Wu, Z., Popescu, O., Badea, T. C. Molecular codes for cell type specification in Brn3 retinal ganglion cells. Proc. Nat. Acad. Sci. 114: E3974-E3983, 2017. Note: Electronic Article. [PubMed: 28465430] [Full Text: https://doi.org/10.1073/pnas.1618551114]
Smith, M. D., Dawson, S. J., Latchman, D. S. Inhibition of neuronal process outgrowth and neuronal specific gene activation by the Brn-3b transcription factor. J. Biol. Chem. 272: 1382-1388, 1997. [PubMed: 8995448] [Full Text: https://doi.org/10.1074/jbc.272.2.1382]
Wagner, K. D., Wagner, N., Vidal, V. P. I., Schley, G., Wilhelm, D., Schedl, A., Englert, C., Scholz, H. The Wilms' tumor gene Wt1 is required for normal development of the retina. EMBO J. 21: 1398-1405, 2002. [PubMed: 11889045] [Full Text: https://doi.org/10.1093/emboj/21.6.1398]
Xiang, M., Zhou, L., Macke, J. P., Yoshioka, T., Hendry, S. H. C., Eddy, R. L., Shows, T. B., Nathans, J. The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons. J. Neurosci. 15: 4762-4785, 1995. [PubMed: 7623109] [Full Text: https://doi.org/10.1523/JNEUROSCI.15-07-04762.1995]
Xiang, M., Zhou, L., Peng, Y.-W., Eddy, R. L., Shows, T. B., Nathans, J. Brn-3b: a POU domain gene expressed in a subset of retinal ganglion cells. Neuron 11: 689-701, 1993. [PubMed: 7691107] [Full Text: https://doi.org/10.1016/0896-6273(93)90079-7]
Xiang, M., Zhou, L.-J., Peng, Y.-W., Byers, M. G., Eddy, R. L., Shows, T. B., Nathans, J. The gene for Brn-3b: a POU-domain protein expressed in retinal ganglion cells is assigned to the q31.2 region of chromosome 4. (Abstract) Human Genome Mapping Workshop 93, Kobe, Japan 1993. P. 7.