The long-term goal of this research proposal is to understand the developmental and molecular mechanisms by which the inner ear sensory epithelium (composed of hair cells and supporting cells) is generated. Dysfunction of the sensory epithelium is a major cause of congenital deafness, age-related hearing loss, and vestibular dysfunction. While there is considerable focus on hair cell development and regeneration, the supporting cells in the sensory epithelium are also essential cell types and underlie many types of deafness and balance disorders. One approach to regenerating both hair cells and supporting cells is to manipulate the cell types that give rise to both cell types, the sensory progenitors. However, little is known about the specification and development of the sensory progenitors. In this proposal we will investigate the role of the Notch signaling pathway during sensory organ formation in the mouse inner ear, focusing on the role of one of the Notch ligands, Jagged1 (JAG1). Previous work has shown that JAG1 is required for sensory progenitor development in the inner ear, although the mechanism is not known. We hypothesize that JAG1 may play a role in the survival, proliferation, or specification of the sensory progenitors as well as in the differentiation of the supporting cells. In order to test these potential roles we will use both loss-of-function (Aim 1) and gain-of-function (Aim 2) approaches in the mouse.
In Aim 1 we will use a conditional loss-of-function Jag1 mouse allele and Cre/loxP technology to generate genetically-modified mouse lines. Using different Cre-expressing mouse strains that delete JAG1 during different stages of development we can define the role that JAG1- mediated Notch signaling plays in sensory progenitor specification and differentiation.
In Aim 2 we will utilize several mouse lines that can be induced to express an activated form of the Notch receptor (NICD) and investigate the consequences of activating Notch at different time points and in different cell types within the inner ear. This proposal will further define the role of JAG1-mediated Notch signaling during sensory development and differentiation within the ear as well as elucidate whether Notch signaling would be an appropriate pathway to manipulate for mammalian regeneration. In humans, genetic, environmental and aging factors contribute to defects in the development, function and survival of the sensory regions within the inner ear, leading to deafness and vestibular dysfunction. The sensory regions in the ear are composed of both hair cells and supporting cells and while the molecular signaling in hair cell development is well studied, little is known about the signals that inform supporting cell development. Results from this proposal will help to define the molecular cascade that underlies the development of the progenitor cells that give rise to both hair cells and supporting cells, and elucidate appropriate pathways to target for regenerative studies in the ear.

Public Health Relevance

In humans, genetic, environmental and aging factors contribute to defects in the development, function and survival of the sensory regions within the inner ear, leading to deafness and vestibular dysfunction. The sensory regions in the ear are composed of both hair cells and supporting cells and while the molecular signaling in hair cell development is well studied, little is known about the signals that inform supporting cell development. Results from this proposal will help to define the molecular cascade that underlies the development of the progenitor cells that give rise to both hair cells and supporting cells, and elucidate appropriate pathways to target for regenerative studies in the ear.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009250-04
Application #
8197187
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2008-12-05
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$368,953
Indirect Cost
$129,373
Name
University of Rochester
Department
Ophthalmology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Deng, Min; Luo, Xiong-jian; Pan, Ling et al. (2014) LMO4 functions as a negative regulator of sensory organ formation in the mammalian cochlea. J Neurosci 34:10072-7
Savoy-Burke, Grace; Gilels, Felicia A; Pan, Wei et al. (2014) Activated notch causes deafness by promoting a supporting cell phenotype in developing auditory hair cells. PLoS One 9:e108160
Kiernan, Amy E (2013) Notch signaling during cell fate determination in the inner ear. Semin Cell Dev Biol 24:470-9
Pan, Wei; Jin, Ying; Chen, Jing et al. (2013) Ectopic expression of activated notch or SOX2 reveals similar and unique roles in the development of the sensory cell progenitors in the mammalian inner ear. J Neurosci 33:16146-57
Pan, Wei; Jin, Ying; Stanger, Ben et al. (2010) Notch signaling is required for the generation of hair cells and supporting cells in the mammalian inner ear. Proc Natl Acad Sci U S A 107:15798-803