PMC:3886832 / 12302-15130 JSONTXT

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Developmental Shifts in Gene Expression\nSince it has been hypothesized that regeneration recapitulates development, understanding temporal shifts in gene expression patterns during the normal development of the auditory system may provide clues to important cellular pathways used for hair cell regeneration. One of the first two studies to use microarray technology to examine gene expression in the inner ear was by Chen and Corey [38,39]. They examined mouse cochleae at two developmental stages (postnatal days 2 and 32) to find differential gene regulation between developing and mature (quiescent) auditory tissues. Since then, gene expression at a number of other developmental stages has been studied in the mouse ear (e.g., E9–E15 [41], P3 and adult [42]). Similarly, Rivolta et al. [40] quantified the time course of gene expression following induced differentiation in conditionally-immortal cells derived from mouse cochleae. These microarray studies confirmed previous evidence that key signaling pathways, such as Notch and Wnt, are important to inner ear development. \nFor example, Notch1 and Notch3, as well as downstream effectors of the notch cascade, such as Hes1 and Hes3, were significantly regulated during differentiation of cochlear cells [40]. Nrarp (Notch-regulated ankyrin repeat protein), which is thought to be part of a negative feedback pathway to attenuate Notch signaling, was upregulated in P3 mouse cochlea relative to adult tissue [42]. A number of Wnt genes were expressed in P2 and/or P32 mouse cochleae, including Wnt-4, Wnt-5a, Wnt-5b, Wnt-7b and Wnt10a [38], but the roles of different Wnt genes vary during development. Four Wnt genes were upregulated only in the early developmental stages of the mouse ear, while eleven were upregulated only in the later stages of inner ear development [39].\nMicroarray studies have also confirmed the importance of cell cycle regulation genes, such as those for cyclin-dependent kinase inhibitors for inner ear development. For instance, p27Kip1, p27Kip2, p19Ink4d and p15Ink4b [38,40,41] were regulated during development of the mouse inner ear. In general, these genes were downregulated in early developmental stages during significant cell proliferation and upregulated in later stages during cell differentiation [40,41]. \nThe power of microarray analysis goes beyond verifying genes that are already known to be expressed in the inner ear, to establishing networks of genes and finding novel genes and pathways. Some examples of such novel genes and pathways discovered via gene expression analysis to be regulated in the inner ear during development include semaphorins [40], Hmga2 (high mobility group AT-hook 2), Nrarp, Prl (prolactin) and Ar (androgen receptor) [42] and circadian rhythm and estrogen receptor signaling pathways [41]."}