Associate Professor - Department of Neuroscience Associate Professor - Department of Molecular and Human Genetics Ph.D., Ludwig Institute for Cancer Research, London, 1992 One Baylor Plaza Baylor College of Medicine Houston TX, 77030 Telephone: 713-798-8743 - Fax: 713-798-7212 Email: akgroves@bcm.edu Website: neuro.bcm.edu/groveslab

My laboratory uses the inner ear as a model system to address fundamental questions in developmental biology and regeneration. The transformation of a simple piece of epithelium - the otic placode - into a sensory organ of extreme morphological complexity provides an opportunity to study questions of competence, induction, pattern formation, cell-type differentiation and morphogenesis. We are using the complementary approaches of chick embryology and mouse genetics to address these problems. We have shown that the FGF and Wnt signaling pathways are critical in inducing the otic placode from embryonic ectoderm, and we are currently characterizing two novel Forkhead transcription factors that may mediate these inductive events. We are examining signaling pathways that specify the formation of the six auditory and balance sense organs of the ear and regulate the fine-grained and beautifully stereotyped pattern of sensory hair cells in these organs. We are also interested in trying to understand the mechanisms of how different sensory organs, such as the organ of Corti in the cochlea, arose during vertebrate evolution.

Sensory hair cells can be destroyed by prolonged exposure to loud noises, or by certain types of antibiotics or chemotherapy drugs. Mammalian hair cells are not replaced after damage, whereas non-mammalian vertebrates such as birds are able to achieve full functional recovery in a matter of weeks by inducing neighboring supporting cells to divide and replace lost hair cells. In an attempt to bring basic research to bear on this clinical problem, we have recently shown that supporting cells in the neonatal mouse cochlea have the capacity to divide and differentiate into hair cells, but that this capacity is largely lost by two weeks of age. This loss of regenerative capacity is due partly to changes in the regulation of cyclin-dependent kinase inhibitors such as p27Kip1. We are also investigating the role of Notch pathway-mediated lateral inhibition in preventing the production of new hair cells after injury.

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Doetzlhofer A, Basch ML, Ohyama T, Gessler M, Groves AK, Segil N. Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev Cell. 2009 Jan;16(1):58-69.

Jayasena CS, Ohyama T, Segil N, Groves AK. Notch signaling augments the canonical Wnt pathway to specify the size of the otic placode. Development. 2008 Jul;135(13):2251-61.

Raft, S., Koundakjian, E.J., Quinones, H., Jayasena, C.S., Goodrich, L.V., Johnson, J.E., Segil, N. and Groves, A.K. (2007). Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development. Development, 134, 4405-4415.

White, P.M., Doetzlhofer, A., Lee, Y.-S., Groves, A.K. and Segil, N. (2006). Cochlear supporting cells retain the ability to divide and transdifferentiate into sensory hair cells. Nature, 441, 984-987.

Arnold, J.S., Braunstein, E.M., Ohyama, T., Groves, A.K., Adams, J.C., Brown, M.C. and Morrow, B.E. (2006). Tissue specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients. Human Molecular Genetics, 15, 1629-39.

Ohyama, T., Mohamed, O.A., Taketo, M.M., Dufort, D. and Groves, A.K. (2006). Wnt signals mediate a fate decision between otic placode and epidermis. Development, 133, 865-875.

Martin, K. and Groves, A.K. (2006). Competence of cranial ectoderm to respond to FGF signaling suggests a two step model of otic placode induction. Development, 133, 877-887.

Kil, S.-H., Streit, A., Brown, S.T., Agrawal, N., Collazo, A., Zile, M.H. and Groves, A.K. (2005). Distinct roles for hindbrain and paraxial mesoderm in the induction and patterning of the inner ear revealed by a study of vitamin A-deficient quail. Developmental Biology 285, 252-271.

Brown, S.P., Wang, J. and Groves, A.K. (2005). Dlx gene expression during chick inner ear development. Journal of Comparative Neurology, 483, 48-65.

Doetzlhofer, A., White, P.M., Johnson, J.E., Segil, N. and Groves, A.K. (2004). In vitro growth and differentiation of mammalian sensory hair cell progenitors: A requirement for EGF and periotic mesenchyme. Developmental Biology 272, 432-447.

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Editorial Board member: Developmental Biology and Developmental Dynamics

Member, Faculty of 1000 (Biology)

Chartered member, NIH AUD study section

Hair Cell Regeneration Initiative Award, National Organization for Hearing Research

Basil O'Connor Scholar Award, March of Dimes Birth Defects Foundation

Long Term Fellowship, Human Frontiers Science Program

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Image 1: Inner ear from a new born mouse derived from a cross between a Pax2-Cre transgenic mouse line developed in our lab and a R26R Cre reporter mouse. The entire inner ear and the vestibulo-acoustic (VIIIth) ganglion are derived from Pax2-expressing progenitor cells. Image 2: Left - An undamaged mouse organ of Corti, showing the stereotyped rows of inner and outer hair cells. Right – A damaged mouse organ of Corti showing significant loss of sensory hair cells. Image 3: Sensory hair cells produced in a cel culture system developed in our lab. The hair cells express Myosin7a (red), Math1 (green) and have actin-rich stereocilia bundles (blue).

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