POU4F1

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. When multiple members of the Brn3 gene class were discovered, it was renamed Brn3.0 and Brn3a by different groups of researchers. 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.

Mice with null mutations ("knockouts") in Brn3a die at birth, due to developmental defects in the nucleus ambiguus, which is essential for respiration.

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.

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. Pou4f1/Isl1 double mutant mice show strong epistatic effects in regulation of many downstream genes in the sensory neurons of double mutant mouse embryos.

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, in which expression of the remaining copy of the Pou4f1 gene is increased in heterozygotes, leading to near-normal expression of its downstream targets. 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, RIT2 and Ewing sarcoma breakpoint region 1.

References

References

1. (Sep 1992). "A novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system". Nucleic Acids Research.
2. "Entrez Gene: POU4F1 POU domain, class 4, transcription factor 1".
3. (Nov 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". Proceedings of the National Academy of Sciences of the United States of America.
4. (Jul 1989). "Expression of a large family of POU-domain regulatory genes in mammalian brain development". Nature.
5. (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.
6. (Nov 1995). "Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursors". Mechanisms of Development.
7. (Dec 1996). "Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons". Nature.
8. (Oct 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". Proceedings of the National Academy of Sciences of the United States of America.
9. (Jan 2001). "Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice". The Journal of Neuroscience.
10. (Aug 2004). "Coordinated regulation of gene expression by Brn3a in developing sensory ganglia". Development.
11. (2007). "POU-domain factor Brn3a regulates both distinct and common programs of gene expression in the spinal and trigeminal sensory ganglia". Neural Development.
12. (Nov 2008). "A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs". Nature Neuroscience.
13. (Jul 2011). "Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation". The Journal of Neuroscience.
14. (Jan 2003). "Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3a". Development.
15. (Feb 1998). "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.
16. (Aug 2003). "Functional interaction between the small GTP-binding protein Rin and the N-terminal of Brn-3a transcription factor". Oncogene.
17. (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.