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. 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 specific role of Math1 has not been determined. In particular, while deletion of Math1 results in an absence of hair cells, it is not clear whether supporting cells, another important cell type within the organ of Corti, are also affected. To examine this possibility, cochleae were obtained from animals containing a targeted mutation in Math1. The presence of supporting cells in these cochleae was then analyzed using a combination of morphological and molecular techniques. Results indicated that development of supporting cells is significantly disrupted in Math1 mutants. To determine the specific effects of Math1, we generated an inducible form of Math1 that was then used to transiently express Math1 in the greater epithelial ridge, a population of epithelial cells within the cochlea that have been shown to be able to develop as hair cells under some circumstances. Transient activation of Math1 in these cells induced the formation of clusters of sensory epithelium that contained both hair cells and associated non-sensory supporting cells. However, while development of hair cells required expression of Math1, supporting cells could develop from either cells expressing Math1, or adjacent cells that did not express Math1. These results demonstrated inductive interactions between adjacent cells play a key role in regulating cell fate and the formation of the sensory epithelium within the cochlea. In a separate series of experiments we examined the role of cellular growth and rearrangement in the formation of cellular pattern within the organ of Corti of the cochlea. Development of the organ of Corti occurs in parallel with extension of the cochlear duct. To examine whether these two events might be linked, we determined the changes in cell size and number of cell contacts within the organ of Corti during the growth of the cochlear duct. Results indicated that the population of cells that will develop as the organ of Corti undergo a period of rearrangement in which the overall shape of the structure changes from short and wide to long and thin. This type of change in shape is referred to as convergence and extension and is consistent with a role for growth of the cochlear duct in the patterning of the organ of Corti.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Intramural Research (Z01)
Project #
1Z01DC000059-05
Application #
6966363
Study Section
(SDN)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2004
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:
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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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