PTEN regulation of the proliferation and differentiation of auditory progenitors through the PTEN/PI3K/Akt-signaling pathway in mice.
PTEN regulation of the proliferation and differentiation of auditory progenitors through the PTEN/PI3K/Akt-signaling pathway in mice.
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DOI：
10.1097/wnr.0000000000000069
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发表时间：
2014-02-12
期刊：
影响因子：
1.7
通讯作者：
Gao J
中科院分区：
文献类型：
--
作者：
Sun C;Zhao J;Jin Y;Hou C;Zong W;Lu T;Li H;Gao J
补充数字内容可在文本中找到。Corti器官是听觉的感觉器官，由一排内毛细胞和三排外毛细胞组成。听觉毛细胞由听觉祖细胞发育而来。毛细胞的发育与包括PTEN在内的几个基因有关。纯合子零突变（PTEN−/−）小鼠在胚胎第9天左右死亡，此时毛细胞非常不成熟。此外，在PTEN杂合敲除小鼠中，发现PTEN调节听觉祖细胞的增殖。然而，人们对这种调控的分子机制知之甚少。在本研究中，我们在小鼠内耳中产生PTEN条件敲除，并研究上述分子机制。我们的研究结果表明，PTEN基因敲除导致毛细胞增加，p-Akt水平升高，p27kip1水平降低。此外，多余毛细胞的存在可以解释为听觉祖细胞从细胞周期中延迟退出。在Pax2-PTEN−/−小鼠耳蜗中，p-Akt水平升高与p27kip1下调相关。减少的p27kip1不能维持听觉祖细胞处于非增殖状态，部分祖细胞继续分裂。因此，额外的祖细胞分化成多余的毛细胞。我们认为PTEN通过p-Akt调控p27kip1，从而调控听觉祖细胞的增殖和分化。
Supplemental Digital Content is available in the text. The organ of Corti, which is the sensory organ of hearing, consists of a single row of inner hair cells and three rows of outer hair cells in mice. The auditory hair cells develop from auditory progenitors. Hair cell development is related to several genes, including PTEN. Homozygous null mutant (PTEN−/−) mice die at around embryonic day 9, when hair cells are extremely immature. Moreover, in heterozygous PTEN knockout mice, it was found that PTEN regulates the proliferation of auditory progenitors. However, little is known about the molecular mechanism underlying this regulation. In the present study, we generated PTEN conditional knockout in the inner ear of mice and studied the aforementioned molecular mechanisms. Our results showed that PTEN knockout resulted in supernumerary hair cells, increased p-Akt level, and decreased p27kip1 level. Furthermore, the presence of supernumerary hair cells could be explained by the delayed withdrawal of auditory progenitors from the cell cycle. The increased p-Akt level correlates with p27kip1 downregulation in the cochlea in the Pax2-PTEN−/− mice. The reduced p27kip1 could not maintain the auditory progenitors in the nonproliferative state and some progenitors continued to divide. Consequently, additional progenitors differentiated into supernumerary hair cells. We suggest that PTEN regulates p27kip1 through p-Akt, thereby regulating the proliferation and differentiation of auditory progenitors.