Disease relevance of Pou4f3

• In contrast, the Brn3a and Brn3c genes, which are expressed later in ganglion cells, appear to be dispensable for ganglion cell development [1].
• Mutations in the POU domain gene Brn-3c causes hearing impairment in both the human and mouse as a result of inner ear hair cell loss [2].
• Two other NRTI drugs, ddl and 3TC, also induced osteoclastogenesis in vitro and induced osteopenia in mice [3].

High impact information on Pou4f3

• Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development [4].
• Mutation of Brn-3.1 results in complete deafness, owing to a failure of hair cells to appear in the inner ear, with subsequent loss of cochlear and vestibular ganglia [4].
• The only known phenotype of the Brn-3.1(-/-) mouse is related to hearing and balance functions, owing to the failure of cochlear and vestibular hair cells to differentiate properly [5].
• Here, we show that normal physiological responses to increased gravity (2G exposure), such as a dramatic drop in body temperature and concomitant circadian adjustment, were completely absent in Brn-3.1(-/-) mice [5].
• By using the Brn 3.1 knockout mouse, which lacks vestibular hair cells, we recently described a major role of the vestibular system in mediating some of these adaptive responses [6].

Biological context of Pou4f3

• BACKGROUND: Ears of Brn3c null mutants develop immature hair cells, identifiable only by certain molecular markers, and undergo apoptosis in neonates [7].
• We show here that during murine embryogenesis, Brn-3c is expressed in postmitotic cells committed to hair cell phenotype but not in mitotic progenitors in the inner ear sensory epithelium [2].
• Our data suggest that Brn-3c may play a role in regulating neurotrophin gene expression in the inner ear [8].
• Similarities and differences among inner retinal neurons revealed by the expression of reporter transgenes controlled by Brn-3a, Brn-3b, and Brn-3c promotor sequences [9].
• We examined regulatory domains in these transcription factors by linking regions of Barhl1 and Brn-3c to the DNA binding domain of the heterologous transcription factor GAL4 and assayed their effect on a heterologous promoter containing GAL4 DNA binding sites by co-transfection into OC-1 and OC-2 cell lines [10].

Anatomical context of Pou4f3

• These results identify Gfi1 as the first downstream target of a hair cell specific transcription factor and suggest that outer hair cell degeneration in Pou4f3 mutants is largely or entirely a result of the loss of expression of Gfi1 [11].
• Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene [11].
• The loss of Gfi1 results in outer hair cell degeneration, which appears comparable to that observed in Pou4f3 mutants [11].
• Moreover, Brn3c had functions in retinal ganglion cell differentiation separate from those of Brn3b [12].
• CONCLUSION: The limited expression of neurotrophins in the cochlea of Brn3c null mice suffices to support many sensory neurons, particularly in the cochlea, until birth [7].

Associations of Pou4f3 with chemical compounds

• Transgenic analyses have revealed the presence of hair-cell-specific promoters in the genes encoding Math1, myosin VIIa, Pou4f3, and the alpha9 subunit of the acetylcholine receptor (alpha9 AChR) [13].
• Two other dideoxynucleosides (ddN) 2'3'-dideoxyinosine (ddl) and 2'3'-dideoxycytidine (ddC) were assessed to determine the specificity of the effect of AZT [14].
• RESULTS: Whereas ddl had no effects, d4T, ZDV and ddC significantly decreased cellular lipid accumulation (by 32%, 46% and 24%, respectively), increased apoptosis and induced mitochondrial depolarization. d4T, ZDV and ddC decreased adipocyte mtDNA (by 64%, 53% and 46%, respectively) and reduced the mtDNA encoded COX II subunit [15].
• METHODS: 3T3-F442A preadipocytes were exposed to stavudine (d4T; 10 microM), zidovudine (ZDV; 1 microM), zalcitabine (ddC; 0.2 microM) or didanosine (ddl; 10 microM) in the absence or presence of uridine 21 days prior to and 7 days after induction of differentiation [15].
• METHODS: The accumulation of free and liposome-encapsulated ddl was determined in murine monocyte-macrophage RAW 264.7 cells and human premonocytoid U937 cells [16].

Other interactions of Pou4f3

• To validate this result, we performed semi-quantitative RT-PCR and in situ hybridizations for Gfi1 on wild-type and Pou4f3 mutant mice [11].
• We directly tested the significance of hair cells or sensory epithelia for fiber guidance in mutants that lose hair cells (Pou4f3) or do not form a posterior crista (Fgf10) [17].
• Transcriptional regulation by Barhl1 and Brn-3c in organ-of-Corti-derived cell lines [10].
• The disruption of the mouse Brn3.1 gene identifies the first mutation affecting sensory hair-cell specification, and mutants for Pax2 and Nkx5.1 genes show their requirement for the development of specific regions of the otic vesicle [18].
• The cells expressed several characteristic features of normal hair cells, including the transcription factor Brn3.1, a functional acetylcholine receptor composed of alpha9 subunits, and the cytoskeletal proteins myosin VI, myosin VIIa, and fimbrin [19].

Analytical, diagnostic and therapeutic context of Pou4f3

• METHODS: The expression of Brn3.1 and alpha9, at different time points under differentiating conditions, was analyzed by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) [20].

References