Multiple roles of the Notch Ligand, Jagged1, in Sensory Development of the Cochlea

Notch 配体 Jagged1 在耳蜗感觉发育中的多重作用

• 批准号: 9911580
• 负责人: Courtney C. Kellogg
• 金额: $ 4.5万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911580
• 关键词: Address; Affect; Alleles; Cells; Cochlea; Cognitive; Data; Defect; Development; Ear; Embryo; Embryonic Development; Future; Genes; Genetic; Goals; Hair Cells; Health; Hearing; Inner Hair Cells; Knock-out; Knockout Mice; Labyrinth; Ligands; Mediating; Medical; Molecular; Morphology; Natural regeneration; Neurons; Notch Signaling Pathway; Organ of Corti; Outer Hair Cells; Pathology; Pattern; Phenotype; Play; Research Personnel; Research Project Grants; Role; Sensory; Sensory Hair; Signal Transduction; Snails; Stem cells; Structure; Supporting Cell; Testing; Time; Training; Work; cell injury; cell type; clinical application; deafness; experience; hearing impairment; inner ear development; loss of function; mutant; notch protein; organ growth; overexpression; progenitor; regenerative; repaired; transcription factor

Abstract Hearing loss is a common health issue that affects millions of people worldwide. Most hearing loss is the result of damage to the organ of Corti, the sensory region of the cochlea in the inner ear. Unfortunately, once damage occurs to critical cell types within the organ of Corti, including hair cells (HC), supporting cells (SC), and neurons, these cells cannot be repaired or regenerated. Understanding the genetic and molecular factors involved in the development of these critical cell types will aid future studies on deriving the regeneration and repair of these cells. Thus, it is necessary to gain a better understanding of the molecular mechanisms involved in inner ear development. Studies have shown that a number of genes, such as the Notch ligand Jag1 and transcription factor Sox2, are critical for sensory formation in the ear. However, it is unclear how these genes act to promote sensory formation. The goal of this proposal is to investigate the role(s) of these genes during cochlear development through two specific aims. In the first aim, I will investigate whether there are multiple roles for JAG1 during cochlear development. My preliminary data suggest that, by knocking JAG1 out at different time points during development, different phenotypes are observed. Early, JAG1 is expressed throughout the sensory region and has been implicated in sensory specification. Previous studies of Jag1 conditional knockouts show loss of sensory cell formation, supporting JAG1 role in sensory progenitor development. Previous data also indicates that Notch may be involved in boundary formation later in development. Thus, I will dissect the functional role(s) of Jag1 during embryonic cochlear development by conditionally knocking out Jag1 at different developmental time points to determine when and how JAG1 is required for sensory development. In the second part of Aim 1, I will determine whether JAG1 is sufficient to expand the pool of sensory progenitors. Previous studies have shown that early ectopic Notch activation, leads to the formation of ectopic sensory regions, indicating Notch is sufficient to drive sensory formation. To test whether JAG1 is the ligand that mediates this role, I will overexpress Jag1 during early otic development and determine whether this can create expanded or ectopic sensory regions. In Aim 2, I will examine the relationship between JAG1 and SOX2. Previous data showed that Notch activation upregulates SOX2, whereas knocking out Jag1 downregulates SOX2, indicating that JAG1 is an upstream molecular regulator of SOX2. Thus, I will investigate whether JAG1 acts via SOX2 to establish sensory progenitor cell formation. To accomplish this, I will overexpress Sox2 in JAG1 loss-of-function embryos to determine if sensory information can be rescued. Results from this proposal will provide a better understanding of the molecular mechanisms underlying cochlear development, which may be key to understanding possible regenerative capacities or approaches.

摘要