Biology:POU4F1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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

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.

Interactions

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

See also

References

  1. ↑ "A novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system". Nucleic Acids Research 20 (18): 4919–25. Sep 1992. doi:10.1093/nar/20.18.4919. PMID 1357630. 
  2. ↑ 2.0 2.1 "Entrez Gene: POU4F1 POU domain, class 4, transcription factor 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5457. 
  3. ↑ 3.0 3.1 "Brn-3.0: a POU-domain protein expressed in the sensory, immune, and endocrine systems that functions on elements distinct from known octamer motifs". Proceedings of the National Academy of Sciences of the United States of America 90 (22): 10841–5. Nov 1993. doi:10.1073/pnas.90.22.10841. PMID 8248179. Bibcode: 1993PNAS...9010841G. 
  4. ↑ "Expression of a large family of POU-domain regulatory genes in mammalian brain development". Nature 340 (6228): 35–41. Jul 1989. doi:10.1038/340035a0. PMID 2739723. Bibcode: 1989Natur.340...35H. 
  5. ↑ "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. Jul 1995. doi:10.1523/JNEUROSCI.15-07-04762.1995. PMID 7623109. 
  6. ↑ "Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursors". Mechanisms of Development 53 (3): 291–304. Nov 1995. doi:10.1016/0925-4773(95)00435-1. PMID 8645597. 
  7. ↑ "Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons". Nature 384 (6609): 574–7. Dec 1996. doi:10.1038/384574a0. PMID 8955272. Bibcode: 1996Natur.384..574M. 
  8. ↑ "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". Proceedings of the National Academy of Sciences of the United States of America 93 (21): 11950–5. Oct 1996. doi:10.1073/pnas.93.21.11950. PMID 8876243. Bibcode: 1996PNAS...9311950X. 
  9. ↑ "Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice". The Journal of Neuroscience 21 (2): 541–9. Jan 2001. doi:10.1523/JNEUROSCI.21-02-00541.2001. PMID 11160433. 
  10. ↑ 10.0 10.1 "Coordinated regulation of gene expression by Brn3a in developing sensory ganglia". Development 131 (16): 3859–70. Aug 2004. doi:10.1242/dev.01260. PMID 15253936. 
  11. ↑ "POU-domain factor Brn3a regulates both distinct and common programs of gene expression in the spinal and trigeminal sensory ganglia". Neural Development 2 (1): 3. 2007. doi:10.1186/1749-8104-2-3. PMID 17239249. 
  12. ↑ "A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs". Nature Neuroscience 11 (11): 1283–93. Nov 2008. doi:10.1038/nn.2209. PMID 18849985. 
  13. ↑ "Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation". The Journal of Neuroscience 31 (27): 9789–99. Jul 2011. doi:10.1523/JNEUROSCI.0901-11.2011. PMID 21734270. 
  14. ↑ "Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3a". Development 130 (1): 111–21. Jan 2003. doi:10.1242/dev.00194. PMID 12441296. 
  15. ↑ "POU transcription factors Brn-3a and Brn-3b interact with the estrogen receptor and differentially regulate transcriptional activity via an estrogen response element". Molecular and Cellular Biology 18 (2): 1029–41. Feb 1998. doi:10.1128/mcb.18.2.1029. PMID 9448000. 
  16. ↑ "Functional interaction between the small GTP-binding protein Rin and the N-terminal of Brn-3a transcription factor". Oncogene 22 (35): 5408–14. Aug 2003. doi:10.1038/sj.onc.1206635. PMID 12934100. 
  17. ↑ "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. 2002. doi:10.4161/cbt.1.4.23. PMID 12432261. 

Further reading

External links

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



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