The goal of the Section on Developmental Neuroscience is to identify the cellular, molecular and genetic factors that play a role in the development of the sensory epithelium of the mammalian cochlea, the organ of Corti. The organ of Corti is comprised of a highly rigorous pattern of specialized cell types that has been shown to be required for normal hearing. During the last year, members of the laboratory concentrated on several different issues related to the development of the organ of Corti. The cochlea develops as an outpocketing from the ventral region of the otocyst that extends to between 1.5 and 3.5 turns depending on the species. In the mouse, the cells that will give rise to the organ of Corti are all present within the duct by E14, even though the cochlea will not obtain its mature length until P0. As a result, the cells that comprise the organ of Corti must undergo significant cellular rearrangements between these time points. To begin to examine these changes, we determined the cellular patterns and number of cell contacts for cells within the developing cochlea at different developmental time points. Results indicate that the epithelium becomes patterned in a gradient that begins in the base of the cochlea and extends along its length. As development proceeds, cells become aligned in rows and the number of contacts per cell begins to decrease. In addition, labeling of small groups of cells within the cochlea indicates that redistribution along the length of the cochlea also plays a role in the development of this cellular pattern. Previous results from our laboratory and other laboratories had identified the basic helix-loop-helix transcription factor (bHLH) Math1 as a key regulator of the development of mechanosensory hair cells. However the factors that regulate the expression of Math1 are poorly understood. To begin to identify genetic factors that could play a role in regulating the expression of Math1 within the cochlea, we examined the expression of members of the ID gene family. ID genes have been shown to negatively regulate expression of bHLH genes by competitively binding to a necessary dimer partner. Our results indicate the ID1 and ID3 are expressed in the developing ear and that the pattern of expression correlates with negative regulation of Math1. Based on these results it seems likely that ID genes can play a role in the regulation of Math1 within the cochlea. One of the most intriguing cell types in the organ of Corti are the pillar cells. These cells comprise a double-row that extends along the length of the cochlea. Previous work from our laboratory had identified a member of the fibroblast growth factor receptor signaling family, FGFR3, as a key regulator of pillar cell differentiation. This year, we examined the potential role of FGFR3 in pillar cell commitment by generating FGFR3 hyperactivity through treatment with two ligands for FGFR3, fibroblast growth factor 2 (FGF2) or FGF17. In both cases, increased activation of FGFR3 lead to an increase in the number of cells that developed as pillar cells. This result suggests that the normally limited number of pillar cells may be regulated through the presence of limiting amounts of FGF ligand within the epithelium. In addition, preliminary results suggest that FGF ligands may be expressed by a single cell type within the cochlea, suggesting that inductive interactions between cell types may play a key role in cellular patterning within the cochlea.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Intramural Research (Z01)
Project #
1Z01DC000059-03
Application #
6674027
Study Section
(SDN)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Deafness & Other Communication Disorders
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Harley, Randall J; Murdy, Joseph P; Wang, Zhirong et al. (2018) Neuronal cell adhesion molecule (NrCAM) is expressed by sensory cells in the cochlea and is necessary for proper cochlear innervation and sensory domain patterning during development. Dev Dyn 247:934-950
Driver, Elizabeth Carroll; Northrop, Amy; Kelley, Matthew W (2017) Cell migration, intercalation and growth regulate mammalian cochlear extension. Development 144:3766-3776
Honda, Keiji; Kim, Sung Huhn; Kelly, Michael C et al. (2017) Molecular architecture underlying fluid absorption by the developing inner ear. Elife 6:
Burns, Joseph C; Kelly, Michael C; Hoa, Michael et al. (2015) Single-cell RNA-Seq resolves cellular complexity in sensory organs from the neonatal inner ear. Nat Commun 6:8557
Coate, Thomas M; Spita, Nathalie A; Zhang, Kaidi D et al. (2015) Neuropilin-2/Semaphorin-3F-mediated repulsion promotes inner hair cell innervation by spiral ganglion neurons. Elife 4:
Kelley, Matthew R; Neath, Ian; Surprenant, Aimee M (2013) Three more semantic serial position functions and a SIMPLE explanation. Mem Cognit 41:600-10
Szarama, Katherine B; Gavara, NĂºria; Petralia, Ronald S et al. (2012) Cytoskeletal changes in actin and microtubules underlie the developing surface mechanical properties of sensory and supporting cells in the mouse cochlea. Development 139:2187-97
Yamamoto, Norio; Okano, Takayuki; Ma, Xuefei et al. (2009) Myosin II regulates extension, growth and patterning in the mammalian cochlear duct. Development 136:1977-86
Driver, Elizabeth Carroll; Pryor, Shannon P; Hill, Patrick et al. (2008) Hedgehog signaling regulates sensory cell formation and auditory function in mice and humans. J Neurosci 28:7350-8
Kelley, Matthew W (2008) Leading Wnt down a PCP path: Cthrc1 acts as a coreceptor in the Wnt-PCP pathway. Dev Cell 15:7-8

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