N-myc controls proliferation, morphogenesis, and patterning of the inner ear.
N-myc controls proliferation, morphogenesis, and patterning of the inner ear.
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DOI：
10.1523/jneurosci.0785-11.2011
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发表时间：
2011-05-11
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影响因子：
--
通讯作者：
Schimmang T
中科院分区：
文献类型：
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作者：
Domínguez-Frutos E;López-Hernández I;Vendrell V;Neves J;Gallozzi M;Gutsche K;Quintana L;Sharpe J;Knoepfler PS;Eisenman RN;Trumpp A;Giráldez F;Schimmang T
Myc家族成员在器官发生过程中调节细胞增殖、大小和分化发挥重要作用。N-myc和c-myc都在内耳发育过程中表达。为了解决它们在小鼠内耳中的功能，我们产生了N-myc或c-myc有条件缺失的小鼠。内耳c-myc缺失不会导致明显的缺陷，而N-myc失活会导致生长减少，原因是缺乏增殖。反过来，N-myc在内耳的错误表达会增加增殖。N-myc小鼠突变体内耳的形态发生受到严重干扰，包括侧耳道缺失，耳蜗与小囊和耳蜗融合，耳蜗生长发育受阻。突变耳蜗的特征是细胞周期结束的细胞数量增加，表达周期蛋白依赖性激酶抑制剂p27Kip1和缺乏周期蛋白D1，这两者都控制毛细胞的有丝分裂后状态。对N-myc突变体耳朵中不同分子标记的分析揭示了Corti的一个包含毛细胞和底层支持细胞的初级器官的发育。然而，分化的细胞不能形成Corti器官所特有的高度有序的结构，而是以行或簇的形式出现，其中有大量的毛细胞。Kölliker的器官是Corti器官附近的一个短暂结构，也是异位毛细胞的潜在来源，在突变的耳朵中缺失。总的来说，我们的数据表明，N-myc在内耳发育过程中调节生长、形态发生和模式形成。
Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea.Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27Kip1 and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The Kölliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells,is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.