Division of Cell Biology and Genetics, House Ear Institute, Los Angeles, California 90057, USA.
J Neurosci. 2010 Nov 10;30(45):15044-51. doi: 10.1523/JNEUROSCI.3547-10.2010.
The mammalian inner ear detects sound with the organ of Corti, an intricately patterned region of the cochlea in which one row of inner hair cells and three rows of outer hair cells are surrounded by specialized supporting cells. The organ of Corti derives from a prosensory domain that runs the length of the cochlear duct and is bounded by two nonsensory domains, Kölliker's organ on the neural side and the outer sulcus on the abneural side. Although much progress has been made in identifying the signals regulating organ of Corti induction and differentiation, less is known about the mechanisms that establish sensory and nonsensory territories in the cochlear duct. Here, we show that a gradient of bone morphogenetic protein (BMP) signaling is established in the abneural-neural axis of the cochlea. Analysis of compound mutants of Alk3/6 type I BMP receptors shows that BMP signaling is necessary for specification of the prosensory domain destined to form the organ of Corti. Reduction of BMP signaling in Alk3/6 compound mutants eliminates both the future outer sulcus and the prosensory domain, with all cells expressing markers of Kölliker's organ. BMP4 upregulates markers of the future outer sulcus and downregulates marker genes of Kölliker's organ in cochlear organ cultures in a dose-dependent manner. Our results suggest BMP signaling is required for patterning sensory and nonsensory tissue in the mammalian cochlea.
哺乳动物内耳通过耳蜗中的柯蒂器(Corti 器官)来探测声音,柯蒂器是耳蜗中一个错综复杂的图案区域,其中一行内毛细胞和三行外毛细胞被专门的支持细胞包围。柯蒂器源自一个前感觉域,该区域沿着耳蜗管的长度延伸,并由两个非感觉域限定,神经侧的科利克氏器(Kölliker's organ)和非神经侧的外嵴(outer sulcus)。虽然在确定调节柯蒂器诱导和分化的信号方面已经取得了很大进展,但对于在耳蜗管中建立感觉和非感觉区域的机制知之甚少。在这里,我们表明,骨形态发生蛋白(BMP)信号在耳蜗的非神经-神经轴上建立了一个梯度。对 Alk3/6 型 I BMP 受体的复合突变体的分析表明,BMP 信号对于指定注定形成柯蒂器的前感觉域是必要的。Alk3/6 复合突变体中 BMP 信号的减少消除了未来的外嵴和前感觉域,所有细胞都表达科利克氏器的标记物。BMP4 以剂量依赖的方式在耳蜗器官培养物中上调未来外嵴的标记物,并下调科利克氏器的标记基因。我们的结果表明,BMP 信号对于哺乳动物耳蜗中感觉和非感觉组织的模式化是必需的。