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:
- 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).
Professor Fritzch is Associate Director of the Aging Mind and Brain Initiative.
Current funding support
2009-2014 NIH/NIDCD R01. Role of MicroRNAs in Mammalian Ear Development and Neurosensory Specification (Soukup PI, Fritzsch Consultant) $17,500
2007-2012 NIH RO1. Genetic and Anatomic Basis for the Fibrosis Syndrome (Engele, Harvard, PI; Fritzsch, Co-I) $138,098 (total for subcontract)
2010-2015 P30 NIH/NIDCD. Iowa Center for Molecular Auditory Neuroscience (Green PI, Dailey, Eberl, Fritzsch, Hansen, Lee Co-Is) $1,699,460 direct costs
Kopecky B, Decook R, Fritzsch B. (2012) Mutational ataxia resulting from abnormal vestibular acquisition and processing is partially compensated for. Behav Neurosci. 126(2):301-13. PubMed PMID: 22309445; PubMed Central PMCID: PMC3314111.
Kopecky B, Johnson S, Schmitz H, Santi P, Fritzsch B. (2012) Scanning thin-sheet laser imaging microscopy elucidates details on mouse ear development. Dev Dyn. 241(3):465-80. PubMed PMID:
Duncan JS, Fritzsch B. (2012) Transforming the vestibular system one molecule at a time: the molecular and developmental basis of vertebrate auditory evolution. Adv Exp Med Biol. 739:173-86. Review. PubMed PMID: 22399402.
Chen Y, Takano-Maruyama M, Fritzsch B, Gaufo GO. (2012) Hoxb1 controls anteroposterior identity of vestibular projection neurons. PLoS One. 7(4):e34762. PubMed PMID: 22485187; PubMed Central PMCID: PMC3317634.
Jahan I, Pan N, Kersigo J, Calisto LE, Morris KA, Kopecky B, Duncan JS, Beisel KW, Fritzsch B. (2012) Expression of Neurog1 instead of Atoh1 can partially rescue organ of Corti cell survival. PLoS One. 7(1):e30853. PubMed PMID: 22292060; PubMed Central PMCID: PMC3265522.
Pan N, Jahan I, Kersigo J, Duncan JS, Kopecky B, Fritzsch B. (2012) A novel Atoh1 \"self-terminating\" mouse model reveals the necessity of proper Atoh1 level and duration for hair cell differentiation and viability. PLoS One. 7(1):e30358. PubMed PMID: 22279587; PubMed Central PMCID: PMC3261193.
Yang T, Kersigo J, Jahan I, Pan N, Fritzsch B. (2011) The molecular basis of making spiral ganglion neurons and connecting them to hair cells of the organ of Corti. Hear Res. 278(1-2):21-33. Review. PubMed PMID: 21414397; PubMed Central PMCID: PMC3130837.
Kopecky B, Santi P, Johnson S, Schmitz H, Fritzsch B. (2011) Conditional deletion of N-Myc disrupts neurosensory and non-sensory development of the ear. Dev Dyn. 240(6):1373-90. PubMed PMID: 21448975; PubMed Central PMCID: PMC3092837.
Fritzsch B, Jahan I, Pan N, Kersigo J, Duncan J, Kopecky B. (2011) Dissecting the molecular basis of organ of Corti development: Where are we now? Hear Res. 276(1-2):16-26. Review. PubMed PMID: 21256948; PubMed Central PMCID: PMC3097286.
Kopecky B, Fritzsch B. (2011) Regeneration of Hair Cells: Making Sense of All the Noise. Pharmaceuticals (Basel). 4(6):848-879. PubMed PMID: 21966254; PubMed Central PMCID: PMC3180915.
Pan N, Jahan I, Kersigo J, Kopecky B, Santi P, Johnson S, Schmitz H, Fritzsch B. (2011) Conditional deletion of Atoh1 using Pax2-Cre results in viable mice without differentiated cochlear hair cells that have lost most of the organ of Corti. Hear Res. 275(1-2):66-80. PubMed PMID: 21146598; PubMed Central PMCID: PMC3065550.
Wong EY, Wang XA, Mak SS, Sae-Pang JJ, Ling KW, Fritzsch B, Sham MH. (2011) Hoxb3 negatively regulates Hoxb1 expression in mouse hindbrain patterning. Dev Biol. 352(2):382-92. PubMed PMID: 21320481.
Weston MD, Pierce ML, Jensen-Smith HC, Fritzsch B, Rocha-Sanchez S, Beisel KW, Soukup GA. (2011) MicroRNA-183 family expression in hair cell development and requirement of microRNAs for hair cell maintenance and survival. Dev Dyn. 240(4):808-19. PubMed PMID: 21360794; PubMed Central PMCID: PMC3072272.
Kersigo J, D\'Angelo A, Gray BD, Soukup GA, Fritzsch B. (2011) The role of sensory organs and the forebrain for the development of the craniofacial shape as revealed by Foxg1-cre-mediated microRNA loss. Genesis. 49(4):326-41. PubMed PMID: 21225654; PubMed Central PMCID: PMC3079063.
Duncan J, Kersigo J, Gray B, Fritzsch B. (2011) Combining lipophilic dye, in situ hybridization, immunohistochemistry, and histology. J Vis Exp. (49). pii: 2451. PubMed PMID: 21445047; PubMed Central PMCID: PMC3197290.
Tao H, Manak JR, Sowers L, Mei X, Kiyonari H, Abe T, Dahdaleh NS, Yang T, Wu S, Chen S, Fox MH, Gurnett C, Montine T, Bird T, Shaffer LG, Rosenfeld JA, McConnell J, Madan-Khetarpal S, Berry-Kravis E, Griesbach H, Saneto RP, Scott MP, Antic D, Reed J, Boland R, Ehaideb SN, El-Shanti H, Mahajan VB, Ferguson PJ, Axelrod JD, Lehesjoki AE, Fritzsch B, Slusarski DC, Wemmie J, Ueno N, Bassuk AG. (2011) Mutations in prickle orthologs cause seizures in flies, mice, and humans. Am J Hum Genet. 88(2):138-49. PubMed PMID: 21276947; PubMed Central PMCID: PMC3035715.
Duncan JS, Lim KC, Engel JD, Fritzsch B. (2011) Limited inner ear morphogenesis and neurosensory development are possible in the absence of GATA3. Int J Dev Biol. 55(3):297-303. PubMed PMID: 21553382.
Duncan JS, Fritzsch B. (2011) Transforming the vestibular system one molecule at a time: the molecular and developmental basis of vertebrate auditory evolution. In: Sensing Systems in Nature, Lopez-Larrea, C. (ed). Pp. 1-14
Fritzsch B, de Caprona D. (2011) Cranial and spinal nerves of fishes: Evolution of the craniate pattern. In: Encyclopedia of Fish Physiology: From Genome to Environment, Vol. X, Farrell, A.P. (ed), Academic Press: San Diego, CA. pp.12-20
Simmons DD, Duncan JS, de Caprona D, Fritzsch B. (2011) Development of the inner ear efferent system. In: Auditory and Vestibular Efferents, Ryugo, D., Fay, R.R., and Popper, A.N. (eds). Springer Science+Business Media, LLC, New York, pp. 187-216.
Sciarretta C, Fritzsch B, Beisel K, Rocha-Sanchez SM, Buniello A, Horn JM, Minichiello L. (2010) PLCγ-activated signalling is essential for TrkB mediated sensory neuron structural plasticity. BMC Dev Biol. 10:103. PubMed PMID: 20932311; PubMed Central PMCID: PMC2964534.
Fritzsch B, Eberl DF, Beisel KW. (2010) The role of bHLH genes in ear development and evolution: revisiting a 10-year-old hypothesis. Cell Mol Life Sci. 67(18):3089-99. Review. PubMed PMID: 20495996.
Bouchard M, de Caprona D, Busslinger M, Xu P, Fritzsch B. (2010) Pax2 and Pax8 cooperate in mouse inner ear morphogenesis and innervation. BMC Dev Biol. 10:89. PubMed PMID: 20727173; PubMed Central PMCID: PMC2939565.
Tonniges J, Hansen M, Duncan J, Bassett MJ, Fritzsch B, Gray BD, Easwaran A, Nichols MG. Photo- and bio-physical characterization of novel violet and near-infrared lipophilic fluorophores for neuronal tracing. J Microsc. 239(2):117-34. PubMed PMID: 20629917.
Jahan I, Pan N, Kersigo J, Fritzsch B. (2010) Neurod1 suppresses hair cell differentiation in ear ganglia and regulates hair cell subtype development in the cochlea. PLoS One. 5(7):e11661. PubMed PMID: 20661473; PubMed Central PMCID: PMC2908541.
Qu Y, Glasco DM, Zhou L, Sawant A, Ravni A, Fritzsch B, Damrau C, Murdoch JN, Evans S, Pfaff SL, Formstone C, Goffinet AM, Chandrasekhar A, Tissir F. Atypical cadherins Celsr1-3 differentially regulate migration of facial branchiomotor neurons in mice. J Neurosci. 30(28):9392-401. PubMed PMID: 20631168; PubMed Central PMCID: PMC3069688.
Jahan I, Kersigo J, Pan N, Fritzsch B. (2010) Neurod1 regulates survival and formation of connections in mouse ear and brain. Cell Tissue Res. 341(1):95-110. Epub 2010 May 30. PubMed PMID: 20512592.
Maklad A, Kamel S, Wong E, Fritzsch B. Development and organization of polarity-specific segregation of primary vestibular afferent fibers in mice. Cell Tissue Res. 340(2):303-21. Epub 2010 Apr 28. PubMed PMID: 20424840; PubMed Central PMCID: PMC2953634.
Fritzsch B, Dillard M, Lavado A, Harvey NL, Jahan I. (2010) Canal cristae growth and fiber extension to the outer hair cells of the mouse ear require Prox1 activity. PLoS One. 5(2):e9377. PubMed PMID: 20186345; PubMed Central PMCID: PMC2826422.
Crapon de Caprona D, Fritzsch B. (2010) Dog genome evolution: a strategy to segregate biogeographic effects from human selection. Proc Natl Acad Sci U S A. 107(4):E11. Epub 2010 Jan 14. PubMed PMID: 20080606; PubMed Central PMCID: PMC2824394.
Brown KK, Reiss JA, Crow K, Ferguson HL, Kelly C, Fritzsch B, Morton CC. (2010) Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35). Hum Genet. 127(1):19-31. PubMed PMID: 19707792; PubMed Central PMCID: PMC2847447.
Elliott KL, Fritzsch B. (2010) Transplantation of Xenopus laevis ears reveals the ability to form afferent and efferent connections with the spinal cord. Int J Dev Biol. 54(10):1443-51. PubMed PMID: 21302254.