POU4F1

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POU class 4 homeobox 1
Identifiers
Symbols POU4F1 ; BRN3A; Oct-T1; RDC-1; brn-3A
External IDs OMIM601632 MGI102525 HomoloGene21255 GeneCards: POU4F1 Gene
RNA expression pattern
PBB GE POU4F1 206940 s at tn.png
PBB GE POU4F1 211341 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5457 18996
Ensembl ENSG00000152192 ENSMUSG00000048349
UniProt Q01851 P17208
RefSeq (mRNA) NM_006237 NM_011143
RefSeq (protein) NP_006228 NP_035273
Location (UCSC) Chr 13:
79.17 – 79.18 Mb
Chr 14:
104.46 – 104.47 Mb
PubMed search [1] [2]

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 POU4F1 gene.[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]

Discovery[edit]

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[edit]

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 transcripion factor class.

Interactions[edit]

POU4F1 has been shown to interact with Estrogen receptor alpha,[15] RIT2[16] and Ewing sarcoma breakpoint region 1.[17]

See also[edit]

References[edit]

  1. ^ Collum RG, Fisher PE, Datta M, Mellis S, Thiele C, Huebner K, Croce CM, Israel MA, Theil T, Moroy T, et al. (Nov 1992). "A novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system". Nucleic Acids Res 20 (18): 4919–25. doi:10.1093/nar/20.18.4919. PMC 334251. PMID 1357630. 
  2. ^ a b "Entrez Gene: POU4F1 POU domain, class 4, transcription factor 1". 
  3. ^ a b Gerrero MR, McEvilly RJ, Turner E, Lin CR, O'Connell S, Jenne KJ, Hobbs MV, Rosenfeld MG (November 1993). "Brn-3.0: a POU-domain protein expressed in the sensory, immune, and endocrine systems that functions on elements distinct from known octamer motifs". Proc. Natl. Acad. Sci. U.S.A. 90 (22): 10841–5. doi:10.1073/pnas.90.22.10841. PMC 47874. PMID 8248179. 
  4. ^ He X, Treacy MN, Simmons DM, Ingraham HA, Swanson LW, Rosenfeld MG (July 1989). "Expression of a large family of POU-domain regulatory genes in mammalian brain development". Nature 340 (6228): 35–41. doi:10.1038/340035a0. PMID 2739723. 
  5. ^ Xiang, M; Zhou, L., Macke, J. P., Yoshioka, T., Hendry, S. H. C., (July 1995). "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 (7 Pt 1): 4762–4785. PMID 7623109. 
  6. ^ Fedtsova NG, Turner EE (November 1995). "Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursors". Mech. Dev. 53 (3): 291–304. doi:10.1016/0925-4773(95)00435-1. PMID 8645597. 
  7. ^ McEvilly RJ, Erkman L, Luo L, Sawchenko PE, Ryan AF, Rosenfeld MG (December 1996). "Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons". Nature 384 (6609): 574–7. doi:10.1038/384574a0. PMID 8955272. 
  8. ^ Xiang M, Gan L, Zhou L, Klein WH, Nathans J (October 1996). "Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling". Proc. Natl. Acad. Sci. U.S.A. 93 (21): 11950–5. doi:10.1073/pnas.93.21.11950. PMC 38164. PMID 8876243. 
  9. ^ Eng SR, Gratwick K, Rhee JM, Fedtsova N, Gan L, Turner EE (January 2001). "Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice". J. Neurosci. 21 (2): 541–9. PMID 11160433. 
  10. ^ a b Eng SR, Lanier J, Fedtsova N, Turner EE (August 2004). "Coordinated regulation of gene expression by Brn3a in developing sensory ganglia". Development 131 (16): 3859–70. doi:10.1242/dev.01260. PMID 15253936. 
  11. ^ Eng SR, Dykes IM, Lanier J, Fedtsova N, Turner EE (2007). "POU-domain factor Brn3a regulates both distinct and common programs of gene expression in the spinal and trigeminal sensory ganglia". Neural Dev 2: 3. doi:10.1186/1749-8104-2-3. PMC 1796875. PMID 17239249. 
  12. ^ Sun Y, Dykes IM, Liang X, Eng SR, Evans SM, Turner EE (November 2008). "A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs". Nat. Neurosci. 11 (11): 1283–93. doi:10.1038/nn.2209. PMC 2605652. PMID 18849985. 
  13. ^ Dykes IM, Tempest L, Lee SI, Turner EE (July 2011). "Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation". J. Neurosci. 31 (27): 9789–99. doi:10.1523/JNEUROSCI.0901-11.2011. PMC 3143040. PMID 21734270. 
  14. ^ Trieu M, Ma A, Eng SR, Fedtsova N, Turner EE (January 2003). "Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3a". Development 130 (1): 111–21. doi:10.1242/dev.00194. PMID 12441296. 
  15. ^ Budhram-Mahadeo V, Parker M, Latchman DS (February 1998). "POU transcription factors Brn-3a and Brn-3b interact with the estrogen receptor and differentially regulate transcriptional activity via an estrogen response element". Mol. Cell. Biol. 18 (2): 1029–41. PMC 108815. PMID 9448000. 
  16. ^ Calissano M, Latchman DS (August 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. PMID 12934100. 
  17. ^ 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 Biol. Ther. 1 (4): 428–32. PMID 12432261. 

Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.