Neurog1 Can Partially Substitute for Atoh1 Function in Hair Cell Differentiation and Maintenance During Organ of Corti Development

Overview

Journal Development

Specialty Biology

Date 2015 Jul 26

PMID 26209643

Citations 30

Authors

Israt Jahan

Ning Pan

Jennifer Kersigo

Bernd Fritzsch

Affiliations

Soon will be listed here.

Abstract

Atoh1, a basic helix-loop-helix (bHLH) transcription factor (TF), is essential for the differentiation of hair cells (HCs), mechanotransducers that convert sound into auditory signals in the mammalian organ of Corti (OC). Previous work demonstrated that replacing mouse Atoh1 with the fly ortholog atonal rescues HC differentiation, indicating functional replacement by other bHLH genes. However, replacing Atoh1 with Neurog1 resulted in reduced HC differentiation compared with transient Atoh1 expression in a 'self-terminating' Atoh1 conditional null mouse (Atoh1-Cre; Atoh1(f/f)). We now show that combining Neurog1 in one allele with removal of floxed Atoh1 in a self-terminating conditional mutant (Atoh1-Cre; Atoh1(f/kiNeurog1)) mouse results in significantly more differentiated inner HCs and outer HCs that have a prolonged longevity of 9 months compared with Atoh1 self-terminating littermates. Stereocilia bundles are partially disorganized, disoriented and not HC type specific. Replacement of Atoh1 with Neurog1 maintains limited expression of Pou4f3 and Barhl1 and rescues HCs quantitatively, but not qualitatively. OC patterning and supporting cell differentiation are also partially disrupted. Diffusible factors involved in patterning are reduced (Fgf8) and factors involved in cell-cell interactions are affected (Jag1, Hes5). Despite the presence of many HCs with stereocilia these mice are deaf, possibly owing to HC and OC patterning defects. This study provides a novel approach to disrupt OC development through modulating the HC-specific intracellular TF network. The resulting disorganized OC indicates that normally differentiated HCs act as 'self-organizers' for OC development and that Atoh1 plays a crucial role to initiate HC stereocilia differentiation independently of HC viability.

Citing Articles

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References

Sheykholeslami K, Thimmappa V, Nava C, Bai X, Yu H, Zheng T . A new mutation of the Atoh1 gene in mice with normal life span allows analysis of inner ear and cerebellar phenotype in aging. PLoS One. 2013; 8(11):e79791. PMC: 3827170. DOI: 10.1371/journal.pone.0079791. View

Self T, Mahony M, FLEMING J, Walsh J, Brown S, Steel K . Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells. Development. 1998; 125(4):557-66. DOI: 10.1242/dev.125.4.557. View

Hertzano R, Shalit E, Rzadzinska A, Dror A, Song L, Ron U . A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells. PLoS Genet. 2008; 4(10):e1000207. PMC: 2543112. DOI: 10.1371/journal.pgen.1000207. View

Johnston Jr R, Desplan C . Interchromosomal communication coordinates intrinsically stochastic expression between alleles. Science. 2014; 343(6171):661-5. PMC: 4134473. DOI: 10.1126/science.1243039. View

Kersigo J, Fritzsch B . Inner ear hair cells deteriorate in mice engineered to have no or diminished innervation. Front Aging Neurosci. 2015; 7:33. PMC: 4364252. DOI: 10.3389/fnagi.2015.00033. View

Zine A, de Ribaupierre F . Notch/Notch ligands and Math1 expression patterns in the organ of Corti of wild-type and Hes1 and Hes5 mutant mice. Hear Res. 2002; 170(1-2):22-31. DOI: 10.1016/s0378-5955(02)00449-5. View

Cai H, Richter C, Chadwick R . Motion analysis in the hemicochlea. Biophys J. 2003; 85(3):1929-37. PMC: 1303364. DOI: 10.1016/S0006-3495(03)74620-7. View

Huh S, Jones J, Warchol M, Ornitz D . Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. PLoS Biol. 2012; 10(1):e1001231. PMC: 3250500. DOI: 10.1371/journal.pbio.1001231. View

Driver E, Sillers L, Coate T, Rose M, Kelley M . The Atoh1-lineage gives rise to hair cells and supporting cells within the mammalian cochlea. Dev Biol. 2013; 376(1):86-98. PMC: 3652277. DOI: 10.1016/j.ydbio.2013.01.005. View

10.

Fritzsch B, Matei V, Nichols D, Bermingham N, Jones K, Beisel K . Atoh1 null mice show directed afferent fiber growth to undifferentiated ear sensory epithelia followed by incomplete fiber retention. Dev Dyn. 2005; 233(2):570-83. PMC: 1242170. DOI: 10.1002/dvdy.20370. View

11.

Rzadzinska A, Nevalainen E, Prosser H, Lappalainen P, Steel K . MyosinVIIa interacts with Twinfilin-2 at the tips of mechanosensory stereocilia in the inner ear. PLoS One. 2009; 4(9):e7097. PMC: 2743196. DOI: 10.1371/journal.pone.0007097. View

12.

Reiprich S, Wegner M . From CNS stem cells to neurons and glia: Sox for everyone. Cell Tissue Res. 2014; 359(1):111-24. DOI: 10.1007/s00441-014-1909-6. View

13.

Jahan I, Pan N, Kersigo J, Fritzsch B . Beyond generalized hair cells: molecular cues for hair cell types. Hear Res. 2012; 297:30-41. PMC: 3624765. DOI: 10.1016/j.heares.2012.11.008. View

14.

Jahan I, Pan N, Elliott K, Fritzsch B . The quest for restoring hearing: Understanding ear development more completely. Bioessays. 2015; 37(9):1016-27. PMC: 4710855. DOI: 10.1002/bies.201500044. View

15.

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

16.

Kiernan A, Xu J, Gridley T . The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet. 2006; 2(1):e4. PMC: 1326221. DOI: 10.1371/journal.pgen.0020004. View

17.

Muller U, Barr-Gillespie P . New treatment options for hearing loss. Nat Rev Drug Discov. 2015; 14(5):346-65. DOI: 10.1038/nrd4533. View

18.

Mogensen M, Rzadzinska A, Steel K . The deaf mouse mutant whirler suggests a role for whirlin in actin filament dynamics and stereocilia development. Cell Motil Cytoskeleton. 2007; 64(7):496-508. PMC: 2682331. DOI: 10.1002/cm.20199. View

19.

Brooker R, Hozumi K, Lewis J . Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development. 2006; 133(7):1277-86. DOI: 10.1242/dev.02284. View

20.

Groves A, Fekete D . Shaping sound in space: the regulation of inner ear patterning. Development. 2011; 139(2):245-57. PMC: 3243092. DOI: 10.1242/dev.067074. View