Unita' di Biologia Cellulare e dello Sviluppo, Dipartimento di Biologia, Universita' di Pisa, Pisa 56127, Italy.
Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6352-7. doi: 10.1073/pnas.1000854107. Epub 2010 Mar 22.
In the developing central nervous system, the cell cycle clock plays a crucial role in determining cell fate specification. A second clock, the circadian oscillator, generates daily rhythms of cell cycle progression. Although these two clocks interact, the mechanisms linking circadian cell cycle progression and cell fate determination are still poorly understood. A convenient system to address this issue is the pineal organ of lower vertebrates, which contains only two neuronal types, photoreceptors and projection neurons. In particular, photoreceptors constitute the core of the pineal circadian system, being able to transduce daily light inputs into the rhythmical production of melatonin. However, the genetic program leading to photoreceptor fate largely remains to be deciphered. Here, we report a previously undescribed function for the homeobox gene Bsx in controlling pineal proliferation and photoreceptor fate in Xenopus. We show that Xenopus Bsx (Xbsx) is expressed rhythmically in postmitotic photoreceptor precursors, reaching a peak during the night, with a cycle that is complementary to the daily rhythms of S-phase entry displayed by pineal cells. Xbsx knockdown results in increased night levels of pineal proliferation, whereas activation of a GR-Xbsx protein flattens the daily rhythms of S-phase entry to the lowest level. Furthermore, evidence is presented that Xbsx is necessary and sufficient to promote a photoreceptor fate. Altogether, these data indicate that Xbsx plays a dual role in contributing to shape the profile of the circadian cell cycle progression and in the specification of pineal photoreceptors, thus acting as a unique link between these two events.
在中枢神经系统的发育过程中，细胞周期时钟在决定细胞命运特化方面起着至关重要的作用。第二个时钟，即生物钟振荡器，产生细胞周期进展的每日节律。尽管这两个时钟相互作用，但将生物钟细胞周期进展与细胞命运决定联系起来的机制仍知之甚少。解决这个问题的一个方便系统是较低等脊椎动物的松果体，它只包含两种神经元类型，即光感受器和投射神经元。特别是，光感受器构成了松果体生物钟的核心，能够将每日的光输入转化为褪黑素的节律性产生。然而，导致光感受器命运的遗传程序在很大程度上仍有待破译。在这里，我们报告了 homeobox 基因 Bsx 在控制非洲爪蟾松果体增殖和光感受器命运方面的一个以前未被描述的功能。我们表明，非洲爪蟾 Bsx（Xbsx）在有丝分裂后光感受器前体中呈节律性表达，在夜间达到高峰，其周期与松果体细胞显示的 S 期进入的每日节律互补。Xbsx 敲低导致夜间松果体增殖水平升高，而 GR-Xbsx 蛋白的激活则将 S 期进入的每日节律降至最低水平。此外，还提供了证据表明，Xbsx 是促进光感受器命运所必需和充分的。总之，这些数据表明，Xbsx 在塑造生物钟细胞周期进展的特征和松果体光感受器的特化方面发挥双重作用，因此是这两个事件之间的独特联系。
