POU3F4, encoding a transcription factor of the POU family, plays a major role in the development of the middle and inner ear. Mutations in this gene are associated with X-linked deafness (DFNX2, DFN3), accounting for about 50% of X-linked non-syndromic hearing loss cases [1].

In Pou3f4 knockout mice, SGN density begins to decline by the end of the first postnatal week, accompanied by significant elevations in SGN apoptosis, suggesting that otic mesenchyme cells expressing Pou3f4 may play a role in maintaining SGN populations during the early postnatal period [2]. Pou3f4-deficient mice also exhibit impairments in learning and memory, and POU3F4 promotes the neuronal differentiation of hippocampal neural stem cells and synapse development, while inhibiting their proliferation [3]. Additionally, Pou3f4-mediated regulation of ephrin-b2 controls temporal bone development in mice, as Efnb2 loss-of-function phenocopies temporal bone abnormalities of Pou3f4 hemizygous null neonates [4]. In Pou3f4-deficient cochlea, differentiation of compartmentalized mesenchyme into specific otic fibrocytes is blocked, and although stria vascularis differentiation is completed, the expression of Kir4.1 channels in strial intermediate cells is lost, which may account for the progressive nature of DFN3 hearing loss [5].

In conclusion, POU3F4 is crucial for the development of the ear and brain. Studies using gene knockout mouse models have revealed its role in maintaining spiral ganglion neuron populations, promoting neuronal differentiation and synaptic development, controlling temporal bone development, and its impact on otic fibrocytes and stria vascularis. These findings enhance our understanding of the pathophysiology of POU3F4-linked hearing loss and other related conditions [1,2,3,4,5].

References:

1. Bernardinelli, Emanuele, Huber, Florian, Roesch, Sebastian, Dossena, Silvia. 2023. Clinical and Molecular Aspects Associated with Defects in the Transcription Factor POU3F4: A Review. In Biomedicines, 11, . doi:10.3390/biomedicines11061695. https://pubmed.ncbi.nlm.nih.gov/37371790/

2. Brooks, Paige M, Rose, Kevin P, MacRae, Meaghan L, Hertzano, Ronna, Coate, Thomas M. 2020. Pou3f4-expressing otic mesenchyme cells promote spiral ganglion neuron survival in the postnatal mouse cochlea. In The Journal of comparative neurology, 528, 1967-1985. doi:10.1002/cne.24867. https://pubmed.ncbi.nlm.nih.gov/31994726/

3. Zhang, Lei, Wang, Jue, Xu, Naijuan, Xu, Min, Zhang, Xinhua. 2024. POU3F4 up-regulates Gli1 expression and promotes neuronal differentiation and synaptic development of hippocampal neural stem cells. In Stem cell research & therapy, 15, 440. doi:10.1186/s13287-024-04043-1. https://pubmed.ncbi.nlm.nih.gov/39563384/

4. Raft, Steven, Coate, Thomas M, Kelley, Matthew W, Crenshaw, E Bryan, Wu, Doris K. 2014. Pou3f4-mediated regulation of ephrin-b2 controls temporal bone development in the mouse. In PloS one, 9, e109043. doi:10.1371/journal.pone.0109043. https://pubmed.ncbi.nlm.nih.gov/25299585/

5. Song, Mee Hyun, Choi, Soo-Young, Wu, Ling, Kim, Un-Kyung, Bok, Jinwoong. 2010. Pou3f4 deficiency causes defects in otic fibrocytes and stria vascularis by different mechanisms. In Biochemical and biophysical research communications, 404, 528-33. doi:10.1016/j.bbrc.2010.12.019. https://pubmed.ncbi.nlm.nih.gov/21144821/