Acampora D, Gulisano M, Broccoli V, Simeone A
International Institute of Genetics and Biophysics, CNR, Via G. Marconi 12, 80125 Naples, Italy.
Prog Neurobiol. 2001 May;64(1):69-95. doi: 10.1016/s0301-0082(00)00042-3.
Most of the gene candidates for the control of developmental programmes that underlie brain morphogenesis in vertebrates are the homologues of Drosophila genes coding for signalling molecules or transcription factors. Among these, the orthodenticle group includes the Drosophila orthodenticle (otd) and the vertebrate Otx1 and Otx2 genes, which are mostly involved in fundamental processes of anterior neural patterning. These genes encode transcription factors that recognise specific target sequences through the DNA binding properties of the homeodomain. In Drosophila, mutations of otd cause the loss of the anteriormost head neuromere where the gene is transcribed, suggesting that it may act as a segmentation "gap" gene. In mouse embryos, the expression patterns of Otx1 and Otx2 have shown a remarkable similarity with the Drosophila counterpart. This suggested that they could be part of a conserved control system operating in the brain and different from that coded by the HOX complexes controlling the hindbrain and spinal cord. To verify this hypothesis a series of mouse models have been generated in which the functions of the murine genes were: (i) fully inactivated, (ii) replaced with each others, (iii) replaced with the Drosophila otd gene. Otx1-/- mutants suffer from epilepsy and are affected by neurological, hormonal, and sense organ defects. Otx2-/- mice are embryonically lethal, they show gastrulation impairments and fail in specifying anterior neural plate. Analysis of the Otx1-/-; Otx2+/- double mutants has shown that a minimal threshold level of the proteins they encode is required for the correct positioning of the midbrain-hindbrain boundary (MHB). In vivo otd/Otx reciprocal gene replacement experiments have provided evidence of a general functional equivalence among otd, Otx1 and Otx2 in fly and mouse. Altogether these data highlight a crucial role for the Otx genes in specification, regionalization and terminal differentiation of rostral central nervous system (CNS) and lead to hypothesize that modification of their regulatory control may have influenced morphogenesis and evolution of the brain.
在脊椎动物中，大多数参与调控大脑形态发生的发育程序的候选基因，都是果蝇中编码信号分子或转录因子的基因的同源物。其中，正齿科基因家族包括果蝇的正齿基因（otd）以及脊椎动物的Otx1和Otx2基因，它们主要参与前脑神经网络形成的基本过程。这些基因编码的转录因子通过同源结构域的DNA结合特性识别特定的靶序列。在果蝇中，otd基因突变会导致该基因转录区域最前端的头部神经节缺失，这表明它可能作为一个分割“间隙”基因发挥作用。在小鼠胚胎中，Otx1和Otx2的表达模式与果蝇中的对应基因表现出显著的相似性。这表明它们可能是在大脑中起作用的保守控制系统的一部分，并且与控制后脑和脊髓的HOX复合体所编码的系统不同。为了验证这一假设，人们构建了一系列小鼠模型，其中小鼠基因的功能分别是：（i）完全失活；（ii）相互替换；（iii）被果蝇otd基因替换。Otx1-/-突变体患有癫痫，并受到神经、激素和感觉器官缺陷的影响。Otx2-/-小鼠胚胎期致死，表现出原肠胚形成障碍，并且在前神经板的特化过程中失败。对Otx1-/-；Otx2+/-双突变体的分析表明，它们编码的蛋白质的最低阈值水平对于中脑-后脑边界（MHB）的正确定位是必需的。体内otd/Otx相互基因替换实验提供了证据，证明otd、Otx1和Otx2在果蝇和小鼠中具有普遍的功能等效性。这些数据共同强调了Otx基因在 Rostral 中枢神经系统（CNS）的特化、区域化和终末分化中的关键作用，并促使人们推测其调控控制的改变可能影响了大脑的形态发生和进化。
