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Gene Review

Pou3f4  -  POU domain, class 3, transcription factor 4

Mus musculus

Synonyms: BRN-4, Brain-4, Brain-specific homeobox/POU domain protein 4, Brn-4, Brn4, ...
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Disease relevance of Pou3f4


High impact information on Pou3f4

  • Neurons comprising the endocrine hypothalamus are disposed in several nuclei that develop in tandem with their ultimate target the pituitary gland, and arise from a primordium in which three related class III POU domain factors, Brn-2, Brn-4, and Brn-1, are initially coexpressed [2].
  • Recently, pilot mapping experiments suggested that the mouse Brn4 / Pou3f4 gene co-segregated with the slf locus on the mouse X chromosome [3].
  • This inversion selectively eliminates the expression of the Brn4 gene in the developing inner ear, but not the neural tube [3].
  • The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear [3].
  • These mapping data, in conjunction with the observation that the vertical head-shaking phenotype of slf mutants is identical to that observed in mice with a targeted deletion of the Brn4 gene, suggested that slf is a mutant allele of the Brn4 gene [3].

Biological context of Pou3f4


Anatomical context of Pou3f4

  • Targeted mutagenesis of the POU-domain gene Brn4/Pou3f4 causes developmental defects in the inner ear [7].
  • Misexpression of Brn-4 by the Idx-1 promoter results in ectopic expression of the proglucagon gene in insulin-expressing pancreatic beta cells, whereas misexpression by rat insulin II promoter did not [5].
  • These results indicated that mutation of the POU-domain gene, Brn4, changed middle-ear sound conduction when measured at the umbo [4].
  • Regulatory regions from the Brn4 promoter direct LACZ expression to the developing forebrain and neural tube [8].
  • The presence of this pathology, the mid-frequency loss in incus sensitivity and the variability in incus velocity among animals suggested that abnormal stapes behavior in Brn4 deficient mice may determine the response of the ossicles, and thus account for the abnormal mid-frequency umbo behavior seen in knockout animals [4].

Associations of Pou3f4 with chemical compounds

  • In the rat, Brn-4 is expressed in 76 and 65% of vasopressin neurons in the paraventricular and supraoptic nuclei, respectively; but in only 10% of corticotropin-releasing factor neurons in the paraventricular nucleus of the hypothalamus [9].
  • The immunoreactivities of p38alpha and p38beta MAPKs were markedly increased in the brain 4 days after KA administration, especially in the areas undergoing selective neuronal loss [10].

Regulatory relationships of Pou3f4

  • In contrast, the regulation of Brn4 which is also expressed in the SON and PVN is independent of Otp function [11].

Other interactions of Pou3f4

  • Thus, in contrast to controls, alpha-cells of mutant mice had protracted expression of Nkx 6.1 and Pdx-1, but did not express Brn-4 [12].
  • The early developmental expression of Brn-4 appears to be a dominant regulator of the glucagon expressing alpha cell lineage, even in the context of the beta cell lineage [5].
  • The mRNAs of two additional POU genes, Emb (POU class VI) and Oct-1 (POU class II), were also expressed in developing muscle and, unlike Brn-4, continued to be expressed in postnatal and adult muscles [6].
  • Hence no strong evidence links Otp and Brn4 in the same regulatory pathway [11].
  • Cdx-2 and Brn-4 are recognized as transcriptional activators for the proglucagon gene [13].

Analytical, diagnostic and therapeutic context of Pou3f4


  1. Retroviral gene transfer and sustained expression of human arylsulfatase A. Learish, R., Ohashi, T., Robbins, P.A., Bahnson, A., Boggs, S.S., Patrene, K., Schwartz, B.E., Gieselmann, V., Barranger, J.A. Gene Ther. (1996) [Pubmed]
  2. Development and survival of the endocrine hypothalamus and posterior pituitary gland requires the neuronal POU domain factor Brn-2. Schonemann, M.D., Ryan, A.K., McEvilly, R.J., O'Connell, S.M., Arias, C.A., Kalla, K.A., Li, P., Sawchenko, P.E., Rosenfeld, M.G. Genes Dev. (1995) [Pubmed]
  3. The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear. Phippard, D., Boyd, Y., Reed, V., Fisher, G., Masson, W.K., Evans, E.P., Saunders, J.C., Crenshaw, E.B. Hum. Mol. Genet. (2000) [Pubmed]
  4. Mutation of the POU-domain gene Brn4/Pou3f4 affects middle-ear sound conduction in the mouse. Samadi, D.S., Saunders, J.C., Crenshaw, E.B. Hear. Res. (2005) [Pubmed]
  5. Brn-4 transcription factor expression targeted to the early developing mouse pancreas induces ectopic glucagon gene expression in insulin-producing beta cells. Hussain, M.A., Miller, C.P., Habener, J.F. J. Biol. Chem. (2002) [Pubmed]
  6. POU homeodomain genes and myogenesis. Dominov, J.A., Miller, J.B. Dev. Genet. (1996) [Pubmed]
  7. Targeted mutagenesis of the POU-domain gene Brn4/Pou3f4 causes developmental defects in the inner ear. Phippard, D., Lu, L., Lee, D., Saunders, J.C., Crenshaw, E.B. J. Neurosci. (1999) [Pubmed]
  8. Regulatory regions from the Brn4 promoter direct LACZ expression to the developing forebrain and neural tube. Heydemann, A., Nguyen, L.C., Crenshaw, E.B. Brain Res. Dev. Brain Res. (2001) [Pubmed]
  9. Binding preferences of the POU domain protein Brain-4: implications for autoregulation. Malik, K.F., Kim, J., Hartman, A.L., Kim, P., Young, W.S. Brain Res. Mol. Brain Res. (1996) [Pubmed]
  10. Delayed induction of p38 MAPKs in reactive astrocytes in the brain of mice after KA-induced seizure. Che, Y., Yu, Y.M., Han, P.L., Lee, J.K. Brain Res. Mol. Brain Res. (2001) [Pubmed]
  11. The murine Otp homeobox gene plays an essential role in the specification of neuronal cell lineages in the developing hypothalamus. Wang, W., Lufkin, T. Dev. Biol. (2000) [Pubmed]
  12. Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased alpha-cell proliferation, and islet neogenesis. Vincent, M., Guz, Y., Rozenberg, M., Webb, G., Furuta, M., Steiner, D., Teitelman, G. Endocrinology (2003) [Pubmed]
  13. Redundant and synergistic effect of Cdx-2 and Brn-4 on regulating proglucagon gene expression. Wang, P., Liu, T., Li, Z., Ma, X., Jin, T. Endocrinology (2006) [Pubmed]
  14. Fetal microchimerism in the maternal mouse brain: a novel population of fetal progenitor or stem cells able to cross the blood-brain barrier? Tan, X.W., Liao, H., Sun, L., Okabe, M., Xiao, Z.C., Dawe, G.S. Stem Cells (2005) [Pubmed]
  15. Abnormal mesenchymal differentiation in the superior semicircular canal of brn4/pou3f4 knockout mice. Sobol, S.E., Teng, X., Crenshaw, E.B. Arch. Otolaryngol. Head Neck Surg. (2005) [Pubmed]
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