Kallunki P, Edelman G M, Jones F S
Department of Neurobiology, The Scripps Research Institute and The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3233-8. doi: 10.1073/pnas.95.6.3233.
The cell adhesion molecule L1 mediates axonal guidance during neural development and mutations in its gene result in severe neurological defects. In previous studies, we identified the promoter for the L1 gene and showed that a neural restrictive silencer element (NRSE) was critical for preventing ectopic expression of L1 during early embryonic development. In the present study, we have investigated the role of the NRSE in the regulation of L1 expression during postnatal development. In gel mobility shift experiments, the NRSE formed DNA-protein complexes with nuclear extracts prepared from the brains of postnatal mice. To examine the influence of the NRSE on postnatal patterns of L1 expression in vivo, we compared the expression of two lacZ transgene constructs, one containing the native L1 gene regulatory sequences (L1lacZ) and another (L1lacZDeltaN) lacking the NRSE. Newborn mice carrying the L1lacZDeltaN showed enhanced beta-galactosidase expression relative to L1lacZ in the brain and ectopic expression in nonneural tissues. In contrast to L1lacZ mice, however, L1lacZDeltaN mice showed an unexpected loss, during postnatal development and in the adult, of beta-galactosidase expression in several neural structures, including the neural retina, cerebellum, cortex, striatum, and hippocampus. These data support the conclusion that the NRSE not only plays a role in the silencing of L1 expression in nonneural tissues during early development but also can function as a silencer and an enhancer of L1 expression in the nervous system of postnatal and adult animals.
细胞黏附分子L1在神经发育过程中介导轴突导向，其基因突变会导致严重的神经缺陷。在先前的研究中，我们鉴定了L1基因的启动子，并表明神经限制性沉默元件（NRSE）对于在胚胎早期发育期间防止L1的异位表达至关重要。在本研究中，我们研究了NRSE在出生后发育过程中对L1表达调控的作用。在凝胶迁移率变动实验中，NRSE与从出生后小鼠大脑制备的核提取物形成DNA-蛋白质复合物。为了检查NRSE对体内L1出生后表达模式的影响，我们比较了两种lacZ转基因构建体的表达，一种包含天然L1基因调控序列（L1lacZ），另一种（L1lacZDeltaN）缺乏NRSE。携带L1lacZDeltaN的新生小鼠相对于L1lacZ在大脑中显示出增强的β-半乳糖苷酶表达，并且在非神经组织中存在异位表达。然而，与L1lacZ小鼠相反，L1lacZDeltaN小鼠在出生后发育期间和成年期在几个神经结构中，包括神经视网膜、小脑、皮质、纹状体和海马体，显示出β-半乳糖苷酶表达意外丧失。这些数据支持这样的结论，即NRSE不仅在早期发育期间在非神经组织中L1表达的沉默中起作用，而且在出生后和成年动物的神经系统中还可以作为L1表达的沉默子和增强子发挥作用。
