In this application we want to resolve some of the molecular and cellular interactions that lead to the formation of the two main sensorineuronal cell types of the ear, the hair cell for mechanoelectric transduction and the sensory neurons for conduction of information from the hair cells to the brain. Using morphological (e.g. immunohistochemistry and DiI labeling) and molecular biological approaches (e.g. in situ hybridization, and RTPCR) we will analyze aspects of 1) cell survival, 2) general cell fate determination, and 3) organ specific cell fate determination.
In AIM 1 we will scrutinize the role played by both location and amount of neurotrophin expression in patterning inner ear innervation. Inner ear sensory neurons express both trkB and trkC receptors. This unique feature will allow us to analyze in a BDNF null mutant simultaneously carrying a neurotrophin transgene (NT3 tgBDNF) for the first time in vivo how both concentration and distribution of a neurotrophin affect the patterning of normal and aberrant nerve fibers.
In AIM 2 we will examine the molecular and cellular interactions of the principle neurogenic bHLH genes expressed in the ear; ngn1, Math1 and NeuroD. We will examine a possible clonal relationship between sensory neurons and hair cells and how the absence of varying combinations of proneuronal bHLH genes affects ear development, in particular the gene expression patterns in supporting cells. In contrast to the brain, this analysis is feasible because only two bHLH genes (Math1, ngn1) determine two neuron-like cells (hair cells, sensory neurons). We will interbreed mutants of ngn1, Math1, and NeuroD to study how ngn1 affects Math1, how ngn1 affects NeuroD, how Math1 affects NeuroD and how double nulls for both ngn1 and Math1 affect formation of the remaining ear.
In AIM 3 we will analyze how BF1 and FGF10 affect the formation of organ specific sensory neurons and sensory epithelia absent in these mutants. We will characterize the expression of the bHLH genes, ngn1 and Math1, in null mutants of BF1 and FGF10. Such information can guide future research on regeneration of these cells in patients suffering sensorineuronal hearing loss and other areas of neuroscience less amenable to such investigations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005590-03
Application #
6793235
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Freeman, Nancy
Project Start
2002-09-01
Project End
2006-06-08
Budget Start
2004-09-01
Budget End
2006-06-08
Support Year
3
Fiscal Year
2004
Total Cost
$339,942
Indirect Cost
Name
Creighton University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Glover, Joel C; Elliott, Karen L; Erives, Albert et al. (2018) Wilhelm His' lasting insights into hindbrain and cranial ganglia development and evolution. Dev Biol :
Fritzsch, Bernd; Elliott, Karen L (2017) Gene, cell, and organ multiplication drives inner ear evolution. Dev Biol 431:3-15
Chagnaud, Boris P; Engelmann, Jacob; Fritzsch, Bernd et al. (2017) Sensing External and Self-Motion with Hair Cells: A Comparison of the Lateral Line and Vestibular Systems from a Developmental and Evolutionary Perspective. Brain Behav Evol 90:98-116
Fritzsch, Bernd; Elliott, Karen L; Glover, Joel C (2017) Gaskell revisited: new insights into spinal autonomics necessitate a revised motor neuron nomenclature. Cell Tissue Res 370:195-209
Elliott, Karen L; Kersigo, Jennifer; Pan, Ning et al. (2017) Spiral Ganglion Neuron Projection Development to the Hindbrain in Mice Lacking Peripheral and/or Central Target Differentiation. Front Neural Circuits 11:25
Fritzsch, Bernd; Duncan, Jeremy S; Kersigo, Jennifer et al. (2016) Neuroanatomical Tracing Techniques in the Ear: History, State of the Art, and Future Developments. Methods Mol Biol 1427:243-62
Fritzsch, Bernd; Jahan, Israt; Pan, Ning et al. (2015) Evolving gene regulatory networks into cellular networks guiding adaptive behavior: an outline how single cells could have evolved into a centralized neurosensory system. Cell Tissue Res 359:295-313
Fritzsch, Bernd; Pan, Ning; Jahan, Israt et al. (2015) Inner ear development: building a spiral ganglion and an organ of Corti out of unspecified ectoderm. Cell Tissue Res 361:7-24
Jahan, Israt; Pan, Ning; Elliott, Karen L et al. (2015) The quest for restoring hearing: Understanding ear development more completely. Bioessays 37:1016-27
Fritzsch, Bernd; Knipper, Marlies; Friauf, Eckhard (2015) Auditory system: development, genetics, function, aging, and diseases. Cell Tissue Res 361:1-6

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