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   Modulating Wnt Signaling Rescues Palate Morphogenesis in Pax9 Mutant Mice  
   
نویسنده li c. ,lan y. ,krumlauf r. ,jiang r.
منبع journal of dental research - 2017 - دوره : 96 - شماره : 11 - صفحه:1273 -1281
چکیده    Cleft palate is a common birth defect caused by disruption of palatogenesis during embryonic development. although mutations disrupting components of the wnt signaling pathway have been associated with cleft lip and palate in humans and mice,the mechanisms involving canonical wnt signaling and its regulation in secondary palate development are not well understood. here,we report that canonical wnt signaling plays an important role in pax9-mediated regulation of secondary palate development. we found that cleft palate pathogenesis in pax9-deficient embryos is accompanied by significantly reduced expression of axin2,an endogenous target of canonical wnt signaling,in the developing palatal mesenchyme,particularly in the posterior regions of the palatal shelves. we found that expression of dkk2,encoding a secreted wnt antagonist,is significantly increased whereas the levels of active β-catenin protein,the essential transcriptional coactivator of canonical wnt signaling,is significantly decreased in the posterior regions of the palatal shelves in embryonic day 13.5 pax9-deficent embryos in comparison with control littermates. we show that small molecule-mediated inhibition of dickkopf (dkk) activity in utero during palatal shelf morphogenesis partly rescued secondary palate development in pax9-deficient embryos. moreover,we found that genetic inactivation of wise,which is expressed in the developing palatal shelves and encodes another secreted antagonist of canonical wnt signaling,also rescued palate morphogenesis in pax9-deficient mice. furthermore,whereas pax9del/del embryos exhibit defects in palatal shelf elevation/reorientation and significant reduction in accumulation of hyaluronic acid - a high molecular extracellular matrix glycosaminoglycan implicated in playing an important role in palatal shelf elevation - 80% of pax9del/del;wise-/- double-mutant mouse embryos exhibit rescued palatal shelf elevation/reorientation,accompanied by restored hyaluronic acid accumulation in the palatal mesenchyme. together,these data identify a crucial role for canonical wnt signaling in acting downstream of pax9 to regulate palate morphogenesis. © international & american associations for dental research 2017.
کلیدواژه cell signaling; cleft palate; craniofacial biology; Sostdc1; transcription factors; Wnt antagonist
آدرس division of developmental biology,cincinnati children's hospital medical center,mlc 7007,3333 burnet avenue,cincinnati,oh, United States, division of developmental biology,cincinnati children's hospital medical center,mlc 7007,3333 burnet avenue,cincinnati,oh,united states,division of plastic surgery,cincinnati children's hospital medical center,cincinnati,oh, United States, stowers institute for medical research,kansas city,mo,united states,department of anatomy and cell biology,university of kansas medical center,kansas city,ks, United States, division of developmental biology,cincinnati children's hospital medical center,mlc 7007,3333 burnet avenue,cincinnati,oh,united states,division of plastic surgery,cincinnati children's hospital medical center,cincinnati,oh, United States
 
     
   
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