Roy Kristine, Kuznicki Kathleen, Wu Qiang, Sun Zhuoxin, Bock Dagmar, Schutz Gunther, Vranich Nancy, Monaghan A Paula
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
J Neurosci. 2004 Sep 22;24(38):8333-45. doi: 10.1523/JNEUROSCI.1148-04.2004.
The tailless (tlx) gene is a forebrain-restricted transcription factor. Tlx mutant animals exhibit a reduction in the size of the cerebral hemispheres and associated structures (Monaghan et al., 1997). Superficial cortical layers are specifically reduced, whereas deep layers are relatively unaltered (Land and Monaghan, 2003). To determine whether the adult laminar phenotype has a developmental etiology and whether it is associated with a change in proliferation/differentiation decisions, we examined the cell cycle and neurogenesis in the embryonic cortex. We found that there is a temporal and regional requirement for the Tlx protein in progenitor cells (PCs). Neurons prematurely differentiate at all rostrocaudal levels up to mid-neurogenesis in mutant animals. Heterozygote animals have an intermediate phenotype indicating there is a threshold requirement for Tlx in early cortical neurogenesis. Our studies indicate that PCs in the ventricular zone are sensitive to loss of Tlx in caudal regions only; however, PCs in the subventricular zone are altered at all rostrocaudal levels in tlx-deficient animals. Furthermore, we found that the cell cycle is shorter from embryonic day 9.5 in tlx-/- embryos. At mid-neurogenesis, the PC population becomes depleted, and late PCs have a longer cell cycle in tlx-deficient animals. Consequently, later generated structures, such as upper cortical layers, the dentate gyrus, and the olfactory bulbs, are severely reduced. These studies indicate that tlx is an essential intrinsic regulator in the decision to proliferate or differentiate in the developing forebrain.
无尾(tlx)基因是一种在前脑受限表达的转录因子。Tlx突变动物的大脑半球及相关结构尺寸减小(莫纳汉等人,1997年)。表层皮质层明显变薄,而深层相对未改变(兰德和莫纳汉,2003年)。为了确定成年期的层状表型是否有发育病因,以及它是否与增殖/分化决定的变化有关,我们研究了胚胎皮质中的细胞周期和神经发生。我们发现祖细胞(PCs)对Tlx蛋白存在时间和区域需求。在突变动物中,直到神经发生中期,所有头尾水平的神经元都过早分化。杂合子动物具有中间表型,表明早期皮质神经发生中Tlx存在阈值需求。我们的研究表明,脑室区的PCs仅对尾侧区域Tlx的缺失敏感;然而,在tlx缺陷动物中,室下区的PCs在所有头尾水平都发生了改变。此外,我们发现tlx-/-胚胎从胚胎第9.5天起细胞周期更短。在神经发生中期,PC群体减少,并且在tlx缺陷动物中晚期PCs具有更长的细胞周期。因此,后期生成的结构,如上层皮质层、齿状回和嗅球,严重减少。这些研究表明,tlx是发育中的前脑增殖或分化决定中必不可少的内在调节因子。