Deciphering the Genetic Interactions Between Pou4f3, Gfi1, and Rbm24 in Maintaining Mouse Cochlear Hair Cell Survival

Overview

Journal Elife

Specialty Biology

Date 2024 Mar 14

PMID 38483314

Authors

Guangqin Wang

Yunpeng Gu

Zhiyong Liu

Affiliations

Soon will be listed here.

Abstract

Mammals harbor a limited number of sound-receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the underlying molecular mechanisms that maintain HC survival is crucial for preventing hearing impairment. Intriguingly, or HCs form initially but then rapidly degenerate, whereas HCs degenerate considerably later. However, the transcriptional cascades involving Pou4f3, Gfi1, and Rbm24 remain undescribed. Here, we demonstrate that expression is completely repressed in HCs but unaltered in HCs, and further that the expression of both POU4F3 and GFI1 is intact in HCs. Moreover, by using in vivo mouse transgenic reporter assays, we identify three enhancers to which POU4F3 binds. Lastly, through in vivo genetic testing of whether Rbm24 restoration alleviates the degeneration of HCs, we show that ectopic Rbm24 alone cannot prevent HCs from degenerating. Collectively, our findings provide new molecular and genetic insights into how HC survival is regulated.

Citing Articles

Irx3/5 Null Deletion in Mice Blocks Cochlea-Saccule Segregation and Disrupts the Auditory Tonotopic Map.

Fritzsch B, Weng X, Yamoah E, Qin T, Hui C, Lebron-Mora L J Comp Neurol. 2024; 532(12):e70008.

PMID: 39655644 PMC: 11629443. DOI: 10.1002/cne.70008.

References

Kuscu C, Parlak M, Tufan T, Yang J, Szlachta K, Wei X . CRISPR-STOP: gene silencing through base-editing-induced nonsense mutations. Nat Methods. 2017; 14(7):710-712. DOI: 10.1038/nmeth.4327. View

Pan Y, Li S, He S, Wang G, Li C, Liu Z . Fgf8: A New Genetic Mouse Model for Specifically Labeling and Sorting Cochlear Inner Hair Cells. Neurosci Bull. 2023; 39(12):1762-1774. PMC: 10661496. DOI: 10.1007/s12264-023-01069-y. View

Xiang M, Gao W, Hasson T, Shin J . Requirement for Brn-3c in maturation and survival, but not in fate determination of inner ear hair cells. Development. 1998; 125(20):3935-46. DOI: 10.1242/dev.125.20.3935. View

Hertzano R, Montcouquiol M, Rashi-Elkeles S, Elkon R, Yucel R, Frankel W . Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene. Hum Mol Genet. 2004; 13(18):2143-53. DOI: 10.1093/hmg/ddh218. View

Yang H, Gan J, Xie X, Deng M, Feng L, Chen X . Gfi1-Cre knock-in mouse line: A tool for inner ear hair cell-specific gene deletion. Genesis. 2010; 48(6):400-6. PMC: 2885521. DOI: 10.1002/dvg.20632. View

Ruel J, Emery S, Nouvian R, Bersot T, Amilhon B, Van Rybroek J . Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am J Hum Genet. 2008; 83(2):278-92. PMC: 2495073. DOI: 10.1016/j.ajhg.2008.07.008. View

Luo Z, Du Y, Li S, Zhang H, Shu M, Zhang D . Three distinct enhancers cooperate for sound receptor hair cell development. Proc Natl Acad Sci U S A. 2022; 119(32):e2119850119. PMC: 9371730. DOI: 10.1073/pnas.2119850119. View

Shu M, Hong D, Lin H, Zhang J, Luo Z, Du Y . Single-cell chromatin accessibility identifies enhancer networks driving gene expression during spinal cord development in mouse. Dev Cell. 2022; 57(24):2761-2775.e6. DOI: 10.1016/j.devcel.2022.11.011. View

Wang G, Li C, He S, Liu Z . Mosaic CRISPR-stop enables rapid phenotyping of nonsense mutations in essential genes. Development. 2021; 148(5). DOI: 10.1242/dev.196899. View

10.

Yu H, Tao L, Llamas J, Wang X, Nguyen J, Trecek T . POU4F3 pioneer activity enables ATOH1 to drive diverse mechanoreceptor differentiation through a feed-forward epigenetic mechanism. Proc Natl Acad Sci U S A. 2021; 118(29). PMC: 8307294. DOI: 10.1073/pnas.2105137118. View

11.

Liu H, Giffen K, Chen L, Henderson H, Cao T, Kozeny G . Molecular and cytological profiling of biological aging of mouse cochlear inner and outer hair cells. Cell Rep. 2022; 39(2):110665. PMC: 9069708. DOI: 10.1016/j.celrep.2022.110665. View

12.

Wallis D, Hamblen M, Zhou Y, Venken K, Schumacher A, Grimes H . The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival. Development. 2002; 130(1):221-32. DOI: 10.1242/dev.00190. View

13.

Kothary R, Clapoff S, Darling S, Perry M, Moran L, Rossant J . Inducible expression of an hsp68-lacZ hybrid gene in transgenic mice. Development. 1989; 105(4):707-14. DOI: 10.1242/dev.105.4.707. View

14.

Fiolka K, Hertzano R, Vassen L, Zeng H, Hermesh O, Avraham K . Gfi1 and Gfi1b act equivalently in haematopoiesis, but have distinct, non-overlapping functions in inner ear development. EMBO Rep. 2006; 7(3):326-33. PMC: 1456886. DOI: 10.1038/sj.embor.7400618. View

15.

Qiu X, Muller U . Sensing sound: Cellular specializations and molecular force sensors. Neuron. 2022; 110(22):3667-3687. PMC: 9671866. DOI: 10.1016/j.neuron.2022.09.018. View

16.

Bermingham N, Hassan B, Price S, Vollrath M, Ben-Arie N, Eatock R . Math1: an essential gene for the generation of inner ear hair cells. Science. 1999; 284(5421):1837-41. DOI: 10.1126/science.284.5421.1837. View

17.

Grifone R, Saquet A, Xu Z, Shi D . Expression patterns of Rbm24 in lens, nasal epithelium, and inner ear during mouse embryonic development. Dev Dyn. 2018; 247(10):1160-1169. DOI: 10.1002/dvdy.24666. View

18.

Wiwatpanit T, Lorenzen S, Cantu J, Foo C, Hogan A, Marquez F . Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. Nature. 2018; 563(7733):691-695. PMC: 6279423. DOI: 10.1038/s41586-018-0570-8. View

19.

Jacques B, Montcouquiol M, Layman E, Lewandoski M, Kelley M . Fgf8 induces pillar cell fate and regulates cellular patterning in the mammalian cochlea. Development. 2007; 134(16):3021-9. DOI: 10.1242/dev.02874. View

20.

Landegger L, Pan B, Askew C, Wassmer S, Gluck S, Galvin A . A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol. 2017; 35(3):280-284. PMC: 5340646. DOI: 10.1038/nbt.3781. View