Battelli Chiara, Nikopoulos George N, Mitchell Jane G, Verdi Joseph M
The Center for Regenerative Medicine, Maine Medical Center Research Institute, 81 Research Drive Scarborough, ME 04074, USA.
Mol Cell Neurosci. 2006 Jan;31(1):85-96. doi: 10.1016/j.mcn.2005.09.003. Epub 2005 Oct 7.
RNA-binding proteins regulate cell fate decisions during nervous system development. The Msi family of RNA-binding proteins is expressed in multipotential neural progenitors, and is required for maintaining cells in a proliferative state. We demonstrate that Msi-1's ability to regulate progenitor maintenance is through the translational inhibition of the cyclin-dependent kinase inhibitor p21WAF-1. Msi-1 ectopic expression increases the proliferation rate and the capacity to regulate p21WAF-1 protein expression, independent of p53. The 3' untranslated region (UTR) of the native p21(WAF-1) mRNA contains a Msi-1 consensus-binding site that permits Msi-1 to directly repress the translation of p21WAF-1 protein. Reduction of Msi-1 through antisense leads to aberrant p21WAF-1 expression, which significantly impairs neural differentiation. A double knockdown for p21WAF-1 and Msi-1 rescues the production of mature MAP+ neurons. Our results further elucidate the symbiotic relationship between cell cycle withdrawal and the onset of differentiation in the developing nervous system, as well as increasing the understanding of the influence that RNA-binding proteins serve in regulating these processes.
RNA结合蛋白在神经系统发育过程中调节细胞命运决定。RNA结合蛋白的Msi家族在多能神经祖细胞中表达，是维持细胞增殖状态所必需的。我们证明，Msi-1调节祖细胞维持的能力是通过对细胞周期蛋白依赖性激酶抑制剂p21WAF-1的翻译抑制实现的。Msi-1异位表达增加了增殖率以及调节p21WAF-1蛋白表达的能力，且不依赖于p53。天然p21（WAF-1）mRNA的3'非翻译区（UTR）包含一个Msi-1共有结合位点，该位点允许Msi-1直接抑制p21WAF-1蛋白的翻译。通过反义技术降低Msi-1会导致p21WAF-1表达异常，这会显著损害神经分化。对p21WAF-1和Msi-1进行双重敲低可挽救成熟MAP+神经元的产生。我们的结果进一步阐明了发育中的神经系统中细胞周期退出与分化开始之间的共生关系，同时也加深了对RNA结合蛋白在调节这些过程中所起作用的理解。
