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

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that in humans is encoded by the POU4F1 gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

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BRN3A (POU4F1) is a class IV POU domain

POU domain

POU is a family of proteins that have well-conserved homeodomains.-Etymology:The acronym POU is derived from the names of three transcription factors:* the Pituitary-specific Pit-1...

-containing transcription factor

Transcription factor

In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

 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.

Discovery

Brn3a was initially discovered in mice based on homology to the prototypal POU transcription factors Pit1 (Pituitary-specific positive transcription factor 1

Pituitary-specific positive transcription factor 1

POU domain, class 1, transcription factor 1 , also known as POU1F1, is a transcription factor for growth hormone.-Interactions:...

, Pou1f1), Oct1 (Pou2f1

POU2F1

POU domain, class 2, transcription factor 1 is a protein that in humans is encoded by the POU2F1 gene.-Interactions:POU2F1 has been shown to interact with SNAPC4, Ku80, Glucocorticoid receptor, Sp1 transcription factor, NPAT, POU2AF1, Host cell factor C1, TATA binding protein, RELA, Nuclear...

) , and the Caenorhabditis elegans factor Unc86, and named Brn3. When multiple members of the Brn3 gene class were dicovered, 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

Red nucleus

The red nucleus is a structure in the rostral midbrain involved in motor coordination. It comprises a caudal magnocellular and a rostral parvocellular part.-Function:...

, nucleus ambiguus

Nucleus ambiguus

The nucleus ambiguus is a region of histologically disparate cells located just dorsal to the inferior olivary nucleus in the lateral portion of the upper medulla...

, inferior olivary nucleus

Inferior olivary nucleus

The inferior olivary nucleus is the largest nucleus situated in the olivary body, part of the medulla oblongata.-Function:It is closely associated with the cerebellum, meaning that it is involved in control and coordination of movements, sensory processing and cognitive tasks likely by encoding the...

, habenula

Habenula

In neuroanatomy, habenula originally denoted the stalk of the pineal gland , but gradually came to refer to a neighboring group of nerve cells with which the pineal gland was believed to be associated, the habenular nucleus...

, 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

LIM domain

LIM domains are protein structural domains, composed of two contiguous zinc finger domains, separated by a two-amino acid residue hydrophobic linker. They are named after their initial discovery in the proteins Lin11, Isl-1 & Mec-3. LIM-domain containing proteins have been shown to play roles in...

 transcription factor ISL1

ISL1

Insulin gene enhancer protein ISL-1 is a protein that in humans is encoded by the ISL1 gene.- Interactions :ISL1 has been shown to interact with Estrogen receptor alpha.-Role in cardiac development:...

 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 transcripion factor class.

Interactions

POU4F1 has been shown to interact

Protein-protein interaction

Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with Estrogen receptor alpha

Estrogen receptor alpha

Estrogen receptor alpha , also known as NR3A1 , is a nuclear receptor that is activated by the sex hormone estrogen...

, RIT2

RIT2

GTP-binding protein Rit2 is a protein that in humans is encoded by the RIT2 gene.-Further reading:...

 and Ewing sarcoma breakpoint region 1

Ewing sarcoma breakpoint region 1

RNA-binding protein EWS is a protein that in humans is encoded by the EWSR1 gene.-Interactions:Ewing sarcoma breakpoint region 1 has been shown to interact with POU4F1, SF1, BARD1, Small nuclear ribonucleoprotein polypeptide C, PTK2B and Zinc finger protein 165.ERG, ATF-1,-External links:* on the...

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