Understanding the molecular pathogenesis of SOX9 Y440X campomelic dysplasia

Human SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia (CD). Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation. Studies in zebrafish and Xenopus suggest that Sox9 may be crucial for specification of the otic placode. In mice, loss of Sox9 results in failure of otic placode invagination. Heterozygous mutations in human SOX9 result in conductive and sensorineural deafness in some CD patients, implying a later morphogenetic role but phenotypic details are limited. Sox9-/- null mice die before morphogenesis of the inner ear is complete, precluding investigation of the role of Sox9 later in ear develop...postprin

Differential and overlapping expression of SOX2 and SOX9 in inner ear development

The 2008 Meeting on Mouse Genetics & Genomics: Development & Disease, Cold Spring Harbor, N.Y., 29 October-2 November 2008

Utility of Hoxb2 enhancer-mediated Cre activity for functional studies in the developing inner ear

The rhombomere 4(r4)-restricted expression of the mouse Hoxb2 gene is regulated by a 1.4-kb enhancer-containing fragment. Here,we show that transgenic mouse lines expressing cre driven by this fragment (B2-r4-Cre), activated the R26R Cre reporter in rhombomere 4 and the second branchial arch, the epithelium of the first branchial arch, apical ectodermal ridge of the limb buds and the tail region. Of particular interest is Cre activity in the developing inner ear. Cre activity was found in the preotic field and otic placode at E8.5 and otocyst at E9.5-E12.5, in the cochleovestibular and facio-acoustic ganglia at E10.5 and the vestibular and spiral ganglia and all the otic epithelia derived from the otocyst at E15.5 and P0. Our data suggest that the B2-r4-Cre transgenic mice provide an important tool for conditional gene manipulation and lineage tracing in the inner ear. In combination with other transgenic lines expressing cre exclusively in the otic vesicle, the relative contributions of the hindbrain, periotic mesenchyme and otic epithelium in otic development can be dissected. © 2009 Wiley-Liss, Inc.link_to_subscribed_fulltex

Dissecting gene function in the developing inner ear using HOXB2-CRE-mediated activity in transgenic mice

The 2008 Meeting on Mouse Genetics & Genomics: Development & Disease, Cold Spring Harbor, N.Y., 29 October-2 November 2008

Differential and overlapping expression pattern of SOX2 and SOX9 in inner ear development

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. © 2009 Elsevier B.V.link_to_OA_fulltex

Aldose reductase regulates hepatic peroxisome proliferator-activated receptor α phosphorylation and activity to impact lipid homeostasis

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 α (PPARα) activity and lipid metabolism. Our results in mouse hepatocyte AML12 cells show that AR overexpression caused strong suppression of PPARα/δ 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 PPARα and ERK1/2. Moreover, AR-induced suppression of PPARα 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 streptozotocin-diabetic mice, AR inhibitor treatment or genetic deficiency of AR resulted in significant dephosphorylation of both PPARα and ERK1/2. With the dephosphorylation of PPARα, 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 PPARα phosphorylation and activity and lipid homeostasis. A significant portion of the AR-induced modulation is achieved through ERK1/2 signaling. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.published_or_final_versio