Abraira Victoria E, Hyun Naomi, Tucker Andrew F, Coling Donald E, Brown M Christian, Lu Cindy, Hoffman Gregory R, Goodrich Lisa V
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2007 Apr 18;27(16):4273-82. doi: 10.1523/JNEUROSCI.3477-06.2007.
During development of the CNS, secreted morphogens of the fibroblast growth factor (FGF) family have multiple effects on cell division, migration, and survival depending on where, when, and how much FGF signal is received. The consequences of misregulating the FGF pathway were studied in a mouse with decreased levels of the FGF antagonist Sef. To uncover effects in the nervous system, we focused on the auditory system, which is accessible to physiological analysis. We found that the mitogen-activated protein kinase pathway is active in the rhombic lip, a germinal zone that generates diverse types of neurons, including the cochlear nucleus complex of the auditory system. Sef is expressed immediately adjacent to the rhombic lip, overlapping with FGF15 and FGFR1, which is also present in the lip itself. This pattern suggests that Sef may normally function in non-rhombic lip cells and prevent them from responding to FGF ligand in the vicinity. Consistent with this idea, overexpression of Sef in chicks decreased the size of the auditory nuclei. Cochlear nucleus defects were also apparent in mice with reduced levels of Sef, with 13% exhibiting grossly dysmorphic cochlear nuclei and 26% showing decreased amounts of GFAP in the cochlear nucleus. Additional evidence for cochlear nucleus defects was obtained by electrophysiological analysis of Sef mutant mice, which have normal auditory thresholds but abnormal auditory brainstem responses. These results show both increases and decreases in Sef levels affect the assembly and function of the auditory brainstem.
在中枢神经系统发育过程中，成纤维细胞生长因子（FGF）家族分泌的形态发生素对细胞分裂、迁移和存活具有多种影响，这取决于FGF信号的接收位置、时间和数量。在FGF拮抗剂Sef水平降低的小鼠中研究了FGF信号通路失调的后果。为了揭示对神经系统的影响，我们聚焦于听觉系统，该系统便于进行生理分析。我们发现丝裂原活化蛋白激酶通路在菱唇中活跃，菱唇是一个生发区，可产生多种类型的神经元，包括听觉系统的耳蜗核复合体。Sef紧邻菱唇表达，与FGF15和FGFR1重叠，FGFR1也存在于菱唇本身。这种模式表明Sef可能通常在非菱唇细胞中发挥作用，并阻止它们对附近的FGF配体作出反应。与此观点一致，在雏鸡中过表达Sef会减小听觉核的大小。在Sef水平降低的小鼠中也明显存在耳蜗核缺陷，13%的小鼠耳蜗核严重畸形，26%的小鼠耳蜗核中GFAP含量减少。通过对Sef突变小鼠的电生理分析获得了耳蜗核缺陷的更多证据，这些小鼠具有正常的听觉阈值，但听觉脑干反应异常。这些结果表明，Sef水平的升高和降低都会影响听觉脑干的组装和功能。
