Laboratory for Cell Asymmetry, at RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuou-ku, Kobe 650-0047, Japan.
Development. 2012 Aug;139(16):3051-62. doi: 10.1242/dev.080002. Epub 2012 Jul 12.
The brain is composed of diverse types of neurons that fulfill distinct roles in neuronal circuits, as manifested by the hippocampus, where pyramidal neurons and granule cells constitute functionally distinct domains: cornu ammonis (CA) and dentate gyrus (DG), respectively. Little is known about how these two types of neuron differentiate during hippocampal development, although a set of transcription factors that is expressed in progenitor cells is known to be required for the survival of granule cells. Here, we demonstrate in mice that Prox1, a transcription factor constitutively expressed in the granule cell lineage, postmitotically functions to specify DG granule cell identity. Postmitotic elimination of Prox1 caused immature DG neurons to lose the granule cell identity and in turn terminally differentiate into the pyramidal cell type manifesting CA3 neuronal identity. By contrast, Prox1 overexpression caused opposing effects on presumptive hippocampal pyramidal cells. These results indicate that the immature DG cell has the potential to become a granule cell or a pyramidal cell, and Prox1 defines the granule cell identity. This bi-potency is lost in mature DG cells, although Prox1 is still required for correct gene expression in DG granule cells. Thus, our data indicate that Prox1 acts as a postmitotic cell fate determinant for DG granule cells over the CA3 pyramidal cell fate and is crucial for maintenance of the granule cell identity throughout the life.
大脑由多种类型的神经元组成，这些神经元在神经元回路中发挥着不同的作用，这在海马体中表现得尤为明显，其中锥体细胞和颗粒细胞分别构成了功能不同的区域：齿状回（DG）和角回（CA）。尽管已知一组在祖细胞中表达的转录因子对于颗粒细胞的存活是必需的，但人们对这两种类型的神经元在海马体发育过程中是如何分化的知之甚少。在这里，我们在小鼠中证明，转录因子 Prox1 在颗粒细胞谱系中持续表达，在后生性细胞中起作用，以特化 DG 颗粒细胞的身份。Prox1 的后生性消除导致不成熟的 DG 神经元丧失颗粒细胞的身份，并转而终末分化为表现 CA3 神经元身份的锥体细胞类型。相比之下，Prox1 的过表达对假定的海马锥体细胞产生了相反的影响。这些结果表明，不成熟的 DG 细胞具有成为颗粒细胞或锥体细胞的潜力，而 Prox1 定义了颗粒细胞的身份。这种双潜能在成熟的 DG 细胞中丧失，尽管 Prox1 仍然是 DG 颗粒细胞中正确基因表达所必需的。因此，我们的数据表明，Prox1 作为 DG 颗粒细胞的后生性细胞命运决定因子，作用超过 CA3 锥体细胞命运，并在整个生命过程中对维持颗粒细胞身份至关重要。
