||Monday, 19 November 2012, 17:00～18:00
||Smart Aging Research Building International Conference Room
||PKA is a Key Mediator of the Dorsoventral Polarity Signals that Drive Inner Ear Morphogenesis
||Distinguished Professor, Department of Neurobiology and Anatomy, Adjunct Professor, Department of Pediatrics, University of Utah School of Medicine
||Harukazu Nakamura Dept. Molecular Neurobiology (ex8585)
||The primordium of the inner ear - a hollow epithelial structure called the otocyst or otic vesicle - gives rise to the membranous labyrinth through regional morphogenesis, a process is which the otocyst is sculpted along the dorsoventral (D-V) axis into a dorsal vestibular chamber, responsible for the perception of motion and body position, and a ventral auditory chamber, responsible for the perception of sound. We are studying the molecular mechanisms underlying this regional morphogenesis by focusing on the roles of SHH (Sonic hedgehog) and BMP (bone morphogenetic protein) signaling. We show that proper formation of inner ear and expression of regional D-V marker genes result from a mutual inhibition between SHH and BMP signaling along the D-V axis of the otocyst. What is the molecular mechanisms of the mutual inhibition? We show that the Gli3 transcriptional activator (Gli3A) accumulates in the ventral otocyst in association with a lower activity of cAMP-dependent protein kinase (PKA). In contrast, Gli3 transcriptional repressor (Gli3R) accumulates in the dorsal otocyst in association with a higher PKA activity. These findings led to the hypothesis that the mutual inhibition between SHH and BMP signaling is mediated by the graded activity of PKA along the D-V axis of the otocyst and in turn gives rise to reciprocal gradients of Gli3A and Gli3R. To test this hypothesis, we perturbed the balance between SHH and BMP signaling along the D-V axis by using in ovo gene trasduction. We show that over expression of Shh decreases PKA activity and results in an increase of Gli3A. In contrast, Bmp4 over expression increases PKA activity and leads to an increase of Gli3R. These results and other ongoing experiments in our lab suggest that dorsovetral patterning and morphogenesis of inner ear is regulated through post transcriptional modification of Gli3, which is determined by graded activity of PKA along D-V axis of otocyst. Supported by the National Institutes of Health.