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Originally published as Genetics Published Articles Ahead of Print on July 29, 2007.
Genetics, Vol. 177, 631-653, September 2007, Copyright © 2007
doi:10.1534/genetics.107.078584
Toward a Systems Biology of Mouse Inner Ear Organogenesis: Gene Expression Pathways, Patterns and Network Analysis
Samin A. Sajan*,
Mark E. Warchol
and
Michael Lovett*,1
* Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63310 and Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri 63310
1 Corresponding author: Division of Human Genetics, Department of Genetics, Washington University School of Medicine, 4566 Scott Ave., St. Louis, MO 63110.
E-mail: lovett{at}genetics.wustl.edu
We describe the most comprehensive study to date on gene expression during mouse inner ear (IE) organogenesis. Samples were microdissected from mouse embryos at E9–E15 in half-day intervals, a period that spans all of IE organogenesis. These included separate dissections of all discernible IE substructures such as the cochlea, utricle, and saccule. All samples were analyzed on high density expression microarrays under strict statistical filters. Extensive confirmatory tests were performed, including RNA in situ hybridizations. More than 5000 genes significantly varied in expression according to developmental stage, tissue, or both and defined 28 distinct expression patterns. For example, upregulation of 315 genes provided a clear-cut "signature" of early events in IE specification. Additional, clear-cut, gene expression signatures marked specific structures such as the cochlea, utricle, or saccule throughout late IE development. Pathway analysis identified 53 signaling cascades enriched within the 28 patterns. Many novel pathways, not previously implicated in IE development, including ß-adrenergic, amyloid, estrogen receptor, circadian rhythm, and immune system pathways, were identified. Finally, we identified positional candidate genes in 54 uncloned nonsyndromic human deafness intervals. This detailed analysis provides many new insights into the spatial and temporal genetic specification of this complex organ system.