The development of the inner ear involves complex processes of morphological changes, patterning and cell fate specification that are under strict molecular control. SOX2 and SOX9 are SOX family transcription factors that are involved in the regulation of one or more of these processes. Previous findings have shown early expression of SOX9 in the otic placode and vesicle at E8.5-E9.5. Here we describe in detail, the expression pattern of SOX9 in the developing mouse inner ear beyond the otocyst stage and compare it with that of SOX2 from E9.5 to E18.5 using double fluorescence immunohistochemistry. We found that SOX9 was widely expressed in the otic epithelium, periotic mesenchyme and cartilaginous otic capsule. SOX2 persistently marked the prosensory and sensory epithelia. During the development of the sensory epithelia, SOX2 was initially expressed in all prosensory regions and later in both the supporting and hair cells up to E15.5, when its expression in hair cells gradually diminished. SOX9 expression overlapped with that of SOX2 in the prosensory and sensory region until E14.5 when its expression was restricted to supporting cells. This initial overlap but subsequent differential expression of SOX2 and SOX9 in the sensory epithelia, suggest that SOX2 and SOX9 may have distinct roles in molecular pathways that direct cells towards different cell fates. KeywordsSOX2; SOX9; Inner ear; Otocyst; Hair cells; Sensory epithelia; Spiral ganglion Results and discussionThe mammalian inner ear is an intricate organ responsible for the perception of sound and balance. The mouse inner ear arises from a thickening of the surface ectoderm called otic placode located adjacent to rhombomeres 5 and 6 of the hindbrain (reviewed in Barald and Kelley, 2004). At E9.0, the otic placode invaginates to form the otic vesicle. Neuroblasts delaminate from the ventral thickening of the otic vesicle and form the otic ganglion which will become the sensory innervation of the inner ear (Rubel and Fritzsch, 2002 vesicle also undergoes a series of morphological changes until it reaches its mature shape by E17 (Morsli et al., 1998).The inner ear consists of six sensory organs: the three cristae in the semi-circular canals and the maculae in the utricle and saccule are responsible for vestibular function; the organ of Corti is responsible for auditory function. The sensory patches in these organs consist of hair and supporting cells. The development of sensory patches in the inner ear requires complex processes of prosensory cell specification and cell fate determination (reviewed in Fritzsch et al., 2006;Kelley, 2007), in which SOX2 and SOX9 are likely to be involved (see below).SOX2 and SOX9 are SOX family transcription factors characterized by a high mobility group (HMG) DNA-binding domain. Mutations in human SOX2 results in anophthalmia, a severe eye malformation, and some patients showed sensorineural hearing loss (Fantes et al., 2003;Hagstrom et al., 2005). SOX2 interacts with EYA1 for prosensory specification (Zou et al., 2008...

Aldose reductase (AR) is implicated in the development of a number of diabetic complications, but the underlying mechanisms remain to be fully elucidated. We performed this study to determine whether and how AR might influence hepatic peroxisome proliferator-activated receptor ␣ (PPAR␣) activity and lipid metabolism. Our results in mouse hepatocyte AML12 cells show that AR overexpression caused strong suppression of PPAR␣/␦ activity (74%, p < 0.001) together with significant down-regulation of mRNA expression for acetyl-CoA oxidase and carnitine palmitoyltransferase-1. These suppressive effects were attenuated by the selective AR inhibitor zopolrestat. Furthermore, AR overexpression greatly increased the levels of phosphorylated PPAR␣ and ERK1/2. Moreover, AR-induced suppression of PPAR␣ activity was attenuated by treatment with an inhibitor for ERK1/2 but not that for phosphoinositide 3-kinase, p38, or JNK. Importantly, similar effects were observed for cells exposed to 25 mM glucose. In streptozotocindiabetic mice, AR inhibitor treatment or genetic deficiency of AR resulted in significant dephosphorylation of both PPAR␣ and ERK1/2. With the dephosphorylation of PPAR␣, hepatic acetyl-CoA oxidase and apolipoprotein C-III mRNA expression was greatly affected and that was associated with substantial reductions in blood triglyceride and nonesterified fatty acid levels. These data indicate that AR plays an important role in the regulation of hepatic PPAR␣ phosphorylation and activity and lipid homeostasis. A significant portion of the AR-induced modulation is achieved through ERK1/2 signaling.

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