POU domain, class 4, transcription factor 1 (POU4F1) also known as brain-specific homeobox/POU domain protein 3A (BRN3A), homeobox/POU domain protein RDC-1 or Oct-T1 is a protein that in humans is encoded by the POU4F1gene.[1][2]
BRN3A (POU4F1) is a class IV POU domain-containing transcription factor highly expressed in the developing peripheral sensory nervous system (dorsal root ganglia, trigeminal ganglion, and hindbrain sensory ganglia), certain regions of the central nervous system, retinal neurons called ganglion cells, and in cells of the B- and T-lymphocytic lineages.[2][3]
Brn3a was initially discovered in mice based on homology to the prototypal POU transcription factors Pit1 (Pituitary-specific positive transcription factor 1, Pou1f1), Oct1 (Pou2f1), and the Caenorhabditis elegans factor Unc86, and named Brn3.[4] When multiple members of the Brn3 gene class were discovered, it was renamed Brn3.0 and Brn3a by different groups of researchers.[3][5] Subsequently, the gene was systematically renamed Pou4f1 in mice and POU4F1 in humans. The protein product is still frequently referred to as Brn3a.
Function
In addition to sensory neurons, in rodents and birds (and presumably humans) Brn3a is expressed in multiple sites in the central nervous system, including the spinal cord, midbrain superior colliculus, red nucleus, nucleus ambiguus, inferior olivary nucleus, habenula, and retina.[6]
Mice with null mutations ("knockouts") in Brn3a die at birth, due to developmental defects in the nucleus ambiguus, which is essential for respiration.[7][8][9]
Brn3a is a transcription factor which acts in development by regulating downstream "target" genes. Microarrays have been used to determine many genes downstream of Brn3a in peripheral sensory neurons.[10][11]
In the sensory neurons Brn3a is co-expressed with the LIM domain transcription factor ISL1 or Islet1, and has many downstream targets in common with Isl1.[12] Pou4f1/Isl1 double mutant mice show strong epistatic effects in regulation of many downstream genes in the sensory neurons of double mutant mouse embryos.[13]
Although the homozygous Brn3a null mutation is lethal at birth in mice, Brn3a null heterozygotes have no known phenotype. i.e. the Brn3a null mutation is completely recessive. This can be explained by gene dosage compensation due to autoregulation,[14] in which expression of the remaining copy of the Pou4f1 gene is increased in heterozygotes, leading to near-normal expression of its downstream targets.[10] The combination of homozygote lethality and dosage compensation in heterozygotes may explain why POU4F1 mutations have not been identified in any human disease, whereas diseases are associated with several other members of the POU domain transcription factor class.
↑He X, Treacy MN, Simmons DM, Ingraham HA, Swanson LW, Rosenfeld MG (Jul 1989). "Expression of a large family of POU-domain regulatory genes in mammalian brain development". Nature. 340 (6228): 35–41. doi:10.1038/340035a0. PMID2739723.
↑Xiang M, Zhou L, Macke JP, Yoshioka T, Hendry SH, Eddy RL, Shows TB, Nathans J (Jul 1995). "The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons". The Journal of Neuroscience. 15 (7 Pt 1): 4762–85. PMID7623109.
↑Fedtsova NG, Turner EE (Nov 1995). "Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursors". Mechanisms of Development. 53 (3): 291–304. doi:10.1016/0925-4773(95)00435-1. PMID8645597.
↑McEvilly RJ, Erkman L, Luo L, Sawchenko PE, Ryan AF, Rosenfeld MG (Dec 1996). "Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons". Nature. 384 (6609): 574–7. doi:10.1038/384574a0. PMID8955272.
↑Eng SR, Gratwick K, Rhee JM, Fedtsova N, Gan L, Turner EE (Jan 2001). "Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice". The Journal of Neuroscience. 21 (2): 541–9. PMID11160433.
↑ 10.010.1Eng SR, Lanier J, Fedtsova N, Turner EE (Aug 2004). "Coordinated regulation of gene expression by Brn3a in developing sensory ganglia". Development. 131 (16): 3859–70. doi:10.1242/dev.01260. PMID15253936.
↑Trieu M, Ma A, Eng SR, Fedtsova N, Turner EE (Jan 2003). "Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3a". Development. 130 (1): 111–21. doi:10.1242/dev.00194. PMID12441296.
↑Calissano M, Latchman DS (Aug 2003). "Functional interaction between the small GTP-binding protein Rin and the N-terminal of Brn-3a transcription factor". Oncogene. 22 (35): 5408–14. doi:10.1038/sj.onc.1206635. PMID12934100.
↑Thomas GR, Latchman DS (2002). "The pro-oncoprotein EWS (Ewing's Sarcoma protein) interacts with the Brn-3a POU transcription factor and inhibits its ability to activate transcription". Cancer Biology & Therapy. 1 (4): 428–32. doi:10.4161/cbt.1.4.23. PMID12432261.
Further reading
Eng SR, Lanier J, Fedtsova N, Turner EE (Aug 2004). "Coordinated regulation of gene expression by Brn3a in developing sensory ganglia". Development. 131 (16): 3859–70. doi:10.1242/dev.01260. PMID15253936.
Xiang M, Zhou L, Macke JP, Yoshioka T, Hendry SH, Eddy RL, Shows TB, Nathans J (Jul 1995). "The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons". The Journal of Neuroscience. 15 (7 Pt 1): 4762–85. PMID7623109.
Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID8889548.
Still IH, Cowell J (1996). "The Brn-3a transcription factor gene (POU4F1) maps close to the locus for the variant late infantile form of neuronal ceroid-lipofuscinosis". Cytogenetics and Cell Genetics. 74 (3): 225–6. doi:10.1159/000134422. PMID8941380.
Smith MD, Dawson SJ, Latchman DS (Jan 1997). "Inhibition of neuronal process outgrowth and neuronal specific gene activation by the Brn-3b transcription factor". The Journal of Biological Chemistry. 272 (2): 1382–8. doi:10.1074/jbc.272.2.1382. PMID8995448.
Frass B, Vassen L, Möröy T (Dec 2002). "Gene expression of the POU factor Brn-3a is regulated by two different promoters". Biochimica et Biophysica Acta. 1579 (2–3): 207–13. doi:10.1016/S0167-4781(02)00540-7. PMID12427558.
Thomas GR, Latchman DS (2003). "The pro-oncoprotein EWS (Ewing's Sarcoma protein) interacts with the Brn-3a POU transcription factor and inhibits its ability to activate transcription". Cancer Biology & Therapy. 1 (4): 428–32. doi:10.4161/cbt.1.4.23. PMID12432261.
Trieu M, Ma A, Eng SR, Fedtsova N, Turner EE (Jan 2003). "Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3a". Development. 130 (1): 111–21. doi:10.1242/dev.00194. PMID12441296.
Ma L, Lei L, Eng SR, Turner E, Parada LF (Aug 2003). "Brn3a regulation of TrkA/NGF receptor expression in developing sensory neurons". Development. 130 (15): 3525–34. doi:10.1242/dev.00582. PMID12810599.
Sindos M, Ndisang D, Pisal N, Chow C, Singer A, Latchman DS (Aug 2003). "Measurement of Brn-3a levels in Pap smears provides a novel diagnostic marker for the detection of cervical neoplasia". Gynecologic Oncology. 90 (2): 366–71. doi:10.1016/S0090-8258(03)00261-0. PMID12893201.
Sindos M, Ndisang D, Pisal N, Chow C, Deery A, Singer A, Latchman D (2004). "Detection of cervical neoplasia using measurement of Brn-3a in cervical smears with persistent minor abnormality". International Journal of Gynecological Cancer. 13 (4): 515–7. doi:10.1046/j.1525-1438.2003.13303.x. PMID12911730.
Calissano M, Latchman DS (Aug 2003). "Functional interaction between the small GTP-binding protein Rin and the N-terminal of Brn-3a transcription factor". Oncogene. 22 (35): 5408–14. doi:10.1038/sj.onc.1206635. PMID12934100.
Gascoyne DM, Thomas GR, Latchman DS (May 2004). "The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1". Oncogene. 23 (21): 3830–40. doi:10.1038/sj.onc.1207497. PMID15021903.
Farooqui-Kabir SR, Budhram-Mahadeo V, Lewis H, Latchman DS, Marber MS, Heads RJ (Nov 2004). "Regulation of Hsp27 expression and cell survival by the POU transcription factor Brn3a". Cell Death and Differentiation. 11 (11): 1242–4. doi:10.1038/sj.cdd.4401478. PMID15272315.
Ndisang D, Faulkes DJ, Gascoyne D, Lee SA, Ripley BJ, Sindos M, Singer A, Budhram-Mahadeo V, Cason J, Latchman DS (Jan 2006). "Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a". Oncogene. 25 (1): 51–60. doi:10.1038/sj.onc.1209006. PMID16247485.
Diss JK, Faulkes DJ, Walker MM, Patel A, Foster CS, Budhram-Mahadeo V, Djamgoz MB, Latchman DS (2006). "Brn-3a neuronal transcription factor functional expression in human prostate cancer". Prostate Cancer and Prostatic Diseases. 9 (1): 83–91. doi:10.1038/sj.pcan.4500837. PMID16276351.