Bernardos Rebecca L, Barthel Linda K, Meyers Jason R, Raymond Pamela A
Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109-1048, USA.
J Neurosci. 2007 Jun 27;27(26):7028-40. doi: 10.1523/JNEUROSCI.1624-07.2007.
Neuronal progenitors in the mammalian brain derive from radial glia or specialized astrocytes. In developing neural retina, radial glia-like Müller cells are generated late in neurogenesis and are not considered to be neuronal progenitors, but they do proliferate after injury and can express neuronal markers, suggesting a latent neurogenic capacity. To examine the neurogenic capacity of retinal glial cells, we used lineage tracing in transgenic zebrafish with a glial-specific promoter (gfap, for glial fibrillary acid protein) driving green fluorescent protein in differentiated Müller glia. We found that all Müller glia in the zebrafish retina express low levels of the multipotent progenitor marker Pax6 (paired box gene 6), and they proliferate at a low frequency in the intact, uninjured retina. Müller glia-derived progenitors express Crx (cone rod homeobox) and are late retinal progenitors that generate the rod photoreceptor lineage in the postembryonic retina. These Müller glia-derived progenitors also remain competent to produce earlier neuronal lineages, in that they respond to loss of cone photoreceptors by specifically regenerating the missing neurons. We conclude that zebrafish Müller glia function as multipotent retinal stem cells that generate retinal neurons by homeostatic and regenerative developmental mechanisms.
哺乳动物大脑中的神经元祖细胞来源于放射状胶质细胞或特化的星形胶质细胞。在发育中的神经视网膜中，放射状胶质样的穆勒细胞在神经发生后期产生，不被认为是神经元祖细胞，但它们在损伤后会增殖并可表达神经元标志物，提示其具有潜在的神经发生能力。为了研究视网膜胶质细胞的神经发生能力，我们在转基因斑马鱼中利用谱系追踪技术，通过胶质细胞特异性启动子（gfap，即胶质纤维酸性蛋白）驱动绿色荧光蛋白在分化的穆勒胶质细胞中表达。我们发现斑马鱼视网膜中的所有穆勒胶质细胞均表达低水平的多能祖细胞标志物Pax6（配对盒基因6），并且它们在完整未受损的视网膜中以低频率增殖。穆勒胶质细胞衍生的祖细胞表达Crx（视锥视杆同源盒），是后期的视网膜祖细胞，可在胚胎后视网膜中产生视杆光感受器谱系。这些穆勒胶质细胞衍生的祖细胞也仍有能力产生早期的神经元谱系，因为它们通过特异性再生缺失神经元来应对视锥光感受器的缺失。我们得出结论，斑马鱼穆勒胶质细胞作为多能视网膜干细胞，通过稳态和再生发育机制产生视网膜神经元。
