This proposal is to examine the ideas that: A) Gfi1 plays a role in neurogenesis and inner ear hair cell development, B) that Gfi1 function is conserved in developmental pathways such that it interacts with Math1, and C) that this interaction is required for the specification and development of inner ear hair cells during mammalian embryogenesis as well as hair cell generation and repair in adult mammals. The first goal is to show that Gfi1 is necessary for the proper development of the inner ear. Mice mutant for Gfi1 will be examined for sensory neuron and inner ear hair cell defects. The second goal is to show that Gfi1 functionally interacts with Math1 in a developmentally conserved pathway. Gfi1 expression analysis in Math1 mutant mice, particularly in the hair cell precursors of the inner ear may provide such evidence. Additionally, Math1 expression will be assessed in Gfi1 mice. The third goal is to examine the ability of Math1 and Gfi1 to play a role in hair cell generation and repair in the inner ear. Expression constructs of the Gfi1 and Math1 have been generated. These constructs will be transfected into gentamicin treated and untreated cochlear and utricular explants to test which combination(s) are most effective at generating and regenerating hair cells. The generation/repair of the hair cells and the maturation of their sensory hair bundles will be determined by microscopy. This is clinically significant as a gene therapy based approach to treat inner ear hair cell loss or damage has immense applications for the hearing and balance impaired.
| Shroyer, Noah F; Wallis, Deeann; Venken, Koen J T et al. (2005) Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev 19:2412-7 |
| Wallis, Deeann; Hamblen, Melanie; Zhou, Yi et al. (2003) The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival. Development 130:221-32 |
