Research Interests

Sensory organs are unique structures in the body plan of all multicellular organisms that allow perception of the environment. Our lab uses the power of mouse genetics to understand the fundamental molecular pathways involved in sensory development and disease, focusing on the eye and the inner ear. As in humans, many of the specialized cell types in the mouse organs, such as hair cells, photoreceptors and ganglion cells, cannot regenerate when damaged due to genetic factors, environmental influences, or normal aging. This can lead to irreversible deafness, vestibular dysfunction and vision loss. Therefore, identifying the key molecules involved in the specification of these cell types and their precursors will be important when developing therapies using stem cells, progenitor cells, or gene therapy as well as in understanding the congenital defects associated with mutations in these genes. The long-term goal of this laboratory is to use advanced mouse genetic approaches, including conditional gene targeting and inducible expression systems, to elucidate key molecular pathways involved in different aspects of sensory development. Currently, our lab is studying the role of the Notch signaling pathway and the transcription factor SOX2 in the development of the eye and the inner ear. By understanding some of the basic molecular processes by which sensory organs form and are maintained, we can begin to develop therapies for prevention, repair and regeneration in sense organ disease.

Projects and Goals

• Dissecting the molecular pathways leading to anterior segment dysgenesis (ASD) of the eye and its contribution to developmental glaucoma

• The role of the Notch ligand JAGGED1 during sensory precursor development in the inner ear

• The role of the transcription factor SOX2 in the development of the prosensory lineage in the inner ear

Publications

Kiernan AE, Nunes F, Wu DK, and Fekete DM. The expression domain of two related homeobox genes defines a compartment in the chicken inner ear that may be involved in semicircular canal formation. Developmental Biology. 1997;191:215-229.

Kiernan AE, Zalzman M, Fuchs H, Hrabe de Angelis M, Balling R, Steel KP, and Avraham KB. Tailchaser (Tlc): A new mouse mutation affecting hair bundle differentiation and hair cell survival. J. Neurocytology. 1999;28:969-985

Nolan P, Peters J, Strivens M, Rogers D, Hagan J, Spurr N, Gray I, Vizor L, Brooker D, Whitehill E, Washbourne R, Hough T, Greenaway S, Hewitt M, Liu X, McCormack S, Pickford K, Selley R, Wells C, Tymowska-Lalanne Z, Roby P, Glenister P, Thornton C, Thaung C, Stevenson J, Arkell R, Mburu P, Hardisty R, Kiernan A, Erven A, Steel KP, Voegeling S, Guenet J, Nickols C, Sadri R, Naase M, Isaacs A, Davies K, Browne M, Fisher EMC, Martin J, Rastan S, Brown SDM, Hunter J. A sytematic genome-wide phenotype-driven mutagenesis programme for gene function studies in the mouse. Nature Genetics. 2000;25:440-443.

Kiernan AE, Ahituv N, Fuchs H, Balling R, Avraham KB, Steel KP, de Angelis MH. The Notch ligand Jagged1 is required for inner ear sensory development. Proceedings of the National Academy of Sciences USA. 2001;98:3873-3878.

Tsai H, Rhodes C, Hardisty RE, Kiernan AE, Roby P, Tymowska-Lalanne Z, Mburu P, Brown SDM. The mouse slalom mutant demonstrates a role for Jagged1 in the neuroepithelial patterning in the organ of Corti. Human Molecular Genetics. 2001;10:507-512.

Alavizadeh A, Kiernan AE, Nolan, P, Lo C, Steel KP, Bucan M. The Wheels mutation in the mouse causes vascular, hindbrain and inner ear defects. Developmental Biology. 2001;234:244-60.

Kiernan AE, Erven A, Voegeling S, Peters J, Nolan P, Hunter J, Bacon Y, Steel KP, Brown SDM, Guénet J. ENU mutagenesis reveals a highly mutable locus on chromosome 4 that affects ear morphogenesis. Mammalian Genome. 2002;13:142-148.

Hulander M, Kiernan AE, Rodrigo Blomqvist S, Carlsson P, Steel, KP, Enerback S. Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in the inner ears of Foxi1 null mutant mice. Development. 2003;130:2013-2025.

Rastan S, Hough T, Kiernan A, Hardisty R, Erven A, Gray IC, Voeling S, Isaacs A, Tsai H, Strivens M, Washbourne R, Thornton C, Greenaway S, Hewitt M, McCormick S, Selley R, Wells C, Tymowska-Lalanne Z, Roby P, Mburu P, Rogers D, Hagan J, Reavill C, Davies K, Glenister P, Fisher EM, Martin J, Vizor L, Bouzyk M, Kelsell D, Guenet JL, Steel KP, Sheardown S, Spurr N, Gray I, Peters J, Nolan PM, Hunter AJ, Brown SD (2004). Towards a mutant map of the mouse--new models of neurological, behavioural, deafness, bone, renal and blood disorders. Genetica. 2004;122:47-9.

Kiernan AE, Pelling AL, Leung KKH, Tang ASP, Bell D, Tease C, Lovell-Badge R, Steel KP, Cheah KSE. Sox2 is required for sensory organ development in the mammalian inner ear. Nature. 2005 Apr 21;434(7036):1031-5

Kiernan AE, Cordes R, Kopan R, Gossler A, Gridley T. The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear. Development. 2005;132:4353-62

Kiernan AE, Xu J, Gridley T. The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet. 2006; 2:e4

Kiernan AE. The paintfill method as a tool for analyzing the three-dimensional structure of the inner ear. Brain Research. 2006 (in the Press)

Reviews

Kiernan AE and Fekete DM. In vivo gene transfer into the embryonic inner ear using retroviral vectors. Audiology and Neuro-otology. 1997;2:12-24.

Brigande JV, Kiernan AE, Gao X, Iten LE, Fekete DM. Molecular genetics of pattern formation in the ear: Do compartment boundaries play a role? Proceedings of the National Academy of Sciences USA. 2000;97:11700-11706.

Book Chapters

Kiernan AE and Steel KP. Mouse homologues for human deafness. In “Genetics in Otorhinolaryngology” (K. Kitamura and K. P. Steel, eds.). Karger, Basel. 2000; 56:233-243

Steel KP, Erven A, Kiernan AE. Mice as models for human hereditary deafness. In, "Genetics and Auditory Disorders". (BJ Keats, AN Popper and RR Fay eds.). New York, Springer. 2002; Chapter 8:247-296

Kiernan AE, Steel KP, Fekete DM. Development of the inner ear. In, “Mouse Development: Patterning, Morphogenesis and Organogenesis”. (P. Tam and J. Rossant, eds.). San Diego, Academic Press. 2002 Chapter 22:539-566.