Ear and hair cell development, regeneration, and evolution
Ongoing research in the Fritzsch laboratory focuses on four main themes:
- Molecular basis of ear development (currently funded by NIH/NIDCD R01)
- Molecular basis of inner ear efferent and brainstem motoneuron formation (currently funded as a subcontract of an NIH R01 with Children's Hospital, Boston)
- Molecular basis of hair cell proliferation, maintenance and regeneration
- Improving multicolor dye tracing techniques (currently funded by NIH/NIMH SBIR II)
Molecular Basis of Ear Development
Research on the molecular basis of ear development analysis, various mutations (knockouts, knockins, transgenic misexpression) of transcription factors (bHLH, Lim homeodomain, GATA, Pax, Eya), or diffusible factors (Fgfs, Wnts, Erbs). This mutational analyses provides in vivo data that help resolve, in collaboration with other laboratories nationally and internationally, the molecular interactions of normal ear development as well as aberrant development underlying congenital ear defects. Superimposed on this proximate analysis is the ultimate question: resolving evolution of the mammalian ear as a transformation of embryonic developmental programs to generate an improved system for sound perception.
Current analysis focuses on:
- The role of miRNA on ear and hair cell development (collaboration with Dr. G. Soukup, Creighton University)
- The role of Lim domain factors (Isl1, Lmx1a) in ear and hair cell development (collaboration with Drs. D. Nichols and K. Beisel, Creighton University; Dr. K. Millen, University of Chicago; Dr. L. Gan, University of Rochester).
- The role of Fgfs, Gata3, Pax2/8, Sox2, Eya 1 and Neurog1 in cochlea neurosensory development (collaborations with Dr. K. Chea, Hong Kong; Dr. P. Xu, Einstein University; Dr. S. Mansour, Salt Lake City; Drs. M. Bouchard and M. Busslinger, Vienna and Montreal).
- The role of neurotrophins in neurosensory support (collaborations with Drs. L. Tessarollo, NCI; L. Minichiello, EMBL; S. Green, U Iowa; K. Beisel, Creighton University; H. Staeker, University of Kansas City)
Molecular Basis of Inner Ear Efferent and Brainstem Motoneuron Formation
The research on brainstem motoneurons is aimed to understand the evolution of novel motor outputs of the brainstem such as the evolution and development of eye muscles and their innervation and the evolution and development of the inner ear efferent system that modifies neurosensory information acquisition in the ear. These novelties are embedded in a fairly rigid framework of rhombomeric hindbrain development governed by the highly conserved homeobox genes as well as other transcription factors.
Current analysis centers around two main themes:
- The molecular basis of ocular muscle formation and connection development in mice (collaboration with Dr. E. Engle, Children Hospital, Boston)
- Molecular basis of inner ear efferent development using conditional mutations of Gata3 or homeobox gene knockout or knockins (collaboration with Drs. G. Gaufo, University of Texas at San Antonio; F. Rijili, Basel; E. Wong, Hong Kong).
- Molecular basis of cochlear nucleus and cerebellar development using conditional mutations for Atoh1 and Neurod1 (collaboration with Drs. S. Maricich and H. Zoghbi, Baylor College of Medicine; Dr. J. Lee and I. Jahan, Boulder and U Iowa)
Molecular Basis of Hair Cell Proliferation, Maintenance, and Regeneration
Research on hair cell development and regeneration can be formally divided into two aspects: molecular basis of proliferation regulation and molecular basis of maintenance and differentiation of hair cells.
Proliferation regulation is pursued through mutational dissection of CDK interactions and retinoblastoma/E2F interactions (collaborations with Drs. M. Barbacid, Madrid; Drs. K. Beisel, D. He and S. Rocha-Sanchez, Creighton University)
Maintenance and differentiation of hair cells is investigated in conditional mutants of Atoh1 and mutants of Pou4f3 (collaboration with Drs. H. Zoghbi, Baylor College; K. Beisel, G. Soukup, D. He and L. Hansen, Creighton University).
Improving Multicolor Dye Tracing Techniques
Research on improvement of lipophilic dyes as well as other tracing techniques is focusing on multicolor labeling techniques in combination with in situ and immunocytochemical analyses to maximize data collection from single mutations for optimized high-throughput phenotypic characterization of mutants. Current work focuses on the various aspects of carbocyanine dyes with the ultimate goal in mind to generate multiple (up to eight) dyes that allow independent labeling of various neuronal populations to investigate simultaneously the interactions of multiple neuronal processes to develop synaptic connections (in collaboration with D. M. Nichols, Creighton University and B. Gray, MITT).