The regulatory mechanism of proliferation and differentiation of the sensory precursor cells during inner ear development and its application for the regenerative medicine.

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We tried to elucidate the regulatory mechanism of the proliferation and differentiation of the sensory progenitor cells during the mammalian inner ear development.At first, we demonstrated the detailed expression patterns of Hes1 and the activated Notch1. In addition, we analyzed the developing inner ear of Hes1 knockout mice, and showed that Notch-Hes1 pathway contributes to the cochlear prosensory formation potentially through the transcriptional down regulation of p27Kip1 (Murata J et al., J Neurosci Res in 2009).In 2008 and 2009 we investigated the developmental expression pattern of the phosphorylated Akt and PTEN, which is an antagonizing factor for the PI3K-Akt signaling pathway. We clarified that the immunoreactivity of PTEN is first observed within the prosensory region in the embryonic cochlear epithelium, and gradually restricted in the hair cell progenitors at the late embryonic stage.The result implied that PI3K/Akt signaling pathway may function for the continuous proliferation and the pluripotency of the inner ear sensory precursor cells.We also started functional analysis of PTEN in 2009, trying to generate inner ear specific PTEN conditional knockout mice. We introduced PTEN-flox mice from the laboratory of professor Tak-Mak in Toronto University and Foxg1-cre mice from Jackson Laboratory.I was transferred from Osaka University to Juntendo University in July 2010. The frozen fertilize ova of the PTEN cko mice were also transferred to Juntendo University. We fused and individuated them and started to analyze the developing inner ear of PTEN cko mice.