Two contrasting roles for Notch activity in chick inner ear development: specification of prosensory patches and lateral inhibition of hair-cell differentiation

Recent studies of inner ear development suggest that hair cells and support cells arise within a common equivalence group by cell-cell interactions mediated by Delta and Notch proteins. We have extended these studies by analyzing the effects of a mutant allele of the zebrafish deltaA gene, deltaA(dx2), which encodes a dominant-negative protein. deltaA(dx2/dx2)homozygous mutants develop with a 5- to 6-fold excess of hair cells and a severe deficiency of support cells. In addition, deltaA(dx2/dx2) mutants show an increased number of cells expressing pax2.1 in regions where hair cells are normally produced. Immunohistological analysis of wild-type and deltaA(dx2/dx2) mutant embryos confirmed that pax2.1 is expressed during the initial stages of hair cell differentiation and is later maintained at high levels in mature hair cells. In contrast, pax2.1 is not expressed in support cells. To address the function of pax2.1, we analyzed hair cell differentiation in no isthmus mutant embryos, which are deficient for pax2.1 function. no isthmus mutant embryos develop with approximately twice the normal number of hair cells. This neurogenic defect correlates with reduced levels of expression of deltaA and deltaD in the hair cells in no isthmus mutants. Analysis of deltaA(dx2/dx2); no isthmus double mutants showed that no isthmus suppresses the deltaA(dx2) phenotype, probably by reducing levels of the dominant-negative mutant protein. This interpretation was supported by analysis of T(msxB)(b220), a deletion that removes the deltaA locus. Reducing the dose of deltaA(dx2) by generating deltaA(dx2)/T(msxB)(b220)trans-heterozygotes weakens the neurogenic effects of deltaA(dx2), whereas T(msxB)(b220) enhances the neurogenic defects of no isthmus. mind bomb, another strong neurogenic mutation that may disrupt reception of Delta signals, causes a 10-fold increase in hair cell production and is epistatic to both no isthmus and deltaA(dx2). These data indicate that deltaA expressed by hair cells normally prevents adjacent cells from adopting the same cell fate, and that pax2.1 is required for normal levels of Delta-mediated lateral inhibition.

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Hes1 is a negative regulator of inner ear hair cell differentiation

Development ◽

10.1242/dev.127.21.4551 ◽

2000 ◽

Vol 127 (21) ◽

pp. 4551-4560 ◽

Cited By ~ 5

Author(s):

J.L. Zheng ◽

J. Shou ◽

F. Guillemot ◽

R. Kageyama ◽

W.Q. Gao

Keyword(s):

Cell Differentiation ◽

Hair Cell ◽

Inner Ear ◽

Cell Fate ◽

Hair Cells ◽

Outer Hair Cells ◽

Negative Regulator ◽

Pcr Analysis ◽

Loss Of Function ◽

Hair Cell Differentiation

Hair cell fate determination in the inner ear has been shown to be controlled by specific genes. Recent loss-of-function and gain-of-function experiments have demonstrated that Math1, a mouse homolog of the Drosophila gene atonal, is essential for the production of hair cells. To identify genes that may interact with Math1 and inhibit hair cell differentiation, we have focused on Hes1, a mammalian hairy and enhancer of split homolog, which is a negative regulator of neurogenesis. We report here that targeted deletion of Hes1 leads to formation of supernumerary hair cells in the cochlea and utricle of the inner ear. RT-PCR analysis shows that Hes1 is expressed in inner ear during hair cell differentiation and its expression is maintained in adulthood. In situ hybridization with late embryonic inner ear tissue reveals that Hes1 is expressed in supporting cells, but not hair cells, of the vestibular sensory epithelium. In the cochlea, Hes1 is selectively expressed in the greater epithelial ridge and lesser epithelial ridge regions which are adjacent to inner and outer hair cells. Co-transfection experiments in postnatal rat explant cultures show that overexpression of Hes1 prevents hair cell differentiation induced by Math1. Therefore Hes1 can negatively regulate hair cell differentiation by antagonizing Math1. These results suggest that a balance between Math1 and negative regulators such as Hes1 is crucial for the production of an appropriate number of inner ear hair cells.

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Hair cell differentiation becomes tissue specific by E9.5 in mouse inner ear

Neuroreport ◽

10.1097/wnr.0b013e3280c1e359 ◽

2007 ◽

Vol 18 (9) ◽

pp. 841-844 ◽

Cited By ~ 2

Author(s):

Tatsunori Sakamoto ◽

Juichi Ito ◽

Raj K. Ladher

Keyword(s):

Cell Differentiation ◽

Hair Cell ◽

Inner Ear ◽

Tissue Specific ◽

Hair Cell Differentiation

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Applying genomics to the avian inner ear: Development of subtractive cDNA resources for exploring sensory function and hair cell regeneration

Genomics ◽

10.1016/j.ygeno.2005.12.014 ◽

2006 ◽

Vol 87 (6) ◽

pp. 801-808 ◽

Cited By ~ 12

Author(s):

R. David Hawkins ◽

Cynthia A. Helms ◽

Julia B. Winston ◽

Mark E. Warchol ◽

Michael Lovett

Keyword(s):

Hair Cell ◽

Inner Ear ◽

Sensory Function ◽

Cell Regeneration ◽

Hair Cell Regeneration ◽

Ear Development ◽

Inner Ear Development ◽

Avian Inner Ear

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Identification with a recombinant antibody of an inner-ear cytokeratin, a marker for hair-cell differentiation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.070050797 ◽

2000 ◽

Vol 97 (9) ◽

pp. 4908-4913 ◽

Cited By ~ 6

Author(s):

J. L. Cyr ◽

A. M. Bell ◽

A. J. Hudspeth

Keyword(s):

Cell Differentiation ◽

Hair Cell ◽

Inner Ear ◽

Recombinant Antibody ◽

Hair Cell Differentiation

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Fgf8 genetic labeling reveals the early specification of vestibular hair cell type in mouse utricle

Development ◽

10.1242/dev.192849 ◽

2020 ◽

Vol 147 (22) ◽

pp. dev192849

Author(s):

Evan M. Ratzan ◽

Anne M. Moon ◽

Michael R. Deans

Keyword(s):

Hair Cell ◽

Inner Ear ◽

Hair Cells ◽

Conditional Knockout ◽

Developmental Model ◽

Type I ◽

Ear Development ◽

Inner Ear Development ◽

Morphological Criteria ◽

Genetic Labeling

ABSTRACTFGF8 signaling plays diverse roles in inner ear development, acting at multiple stages from otic placode induction to cellular differentiation in the organ of Corti. As a secreted morphogen with diverse functions, Fgf8 expression is likely to be spatially restricted and temporally dynamic throughout inner ear development. We evaluated these characteristics using genetic labeling mediated by Fgf8mcm gene-targeted mice and determined that Fgf8 expression is a specific and early marker of Type-I vestibular hair cell identity. Fgf8mcm expression initiates at E11.5 in the future striolar region of the utricle, labeling hair cells following EdU birthdating, and demonstrates that sub-type identity is determined shortly after terminal mitosis. This early fate specification is not apparent using markers or morphological criteria that are not present before birth in the mouse. Although analyses of Fgf8 conditional knockout mice did not reveal developmental phenotypes, the restricted pattern of Fgf8 expression suggests that functionally redundant FGF ligands may contribute to vestibular hair cell differentiation and supports a developmental model in which Type-I and Type-II hair cells develop in parallel rather than from an intermediate precursor.

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