Role for zic genes in the developing midbrain.

脊椎动物大脑惊人的功能和解剖复杂性逐渐出现， 胚胎从最初均匀的细胞区域发育而成。我们想了解 大脑发育，特别是沿大脑背侧/腹侧轴沿着形成不对称 原基本研究将探讨两个相关的转录因子zic 2和zic 5在背侧神经节细胞中的作用， 大脑形成这两个基因的重要功能已经在几种脊椎动物中得到证实， 但其机制尚不清楚。在人类中，zic 2和zic 5的突变已经被因果联系起来。 两种常见的出生缺陷：露脑畸形和前脑无裂畸形。zic基因的表达仅限于 神经管的背侧部分，这种限制对于它们的正确功能至关重要。 尽管它们的重要性显而易见，但脊椎动物的调节和功能的分子机制 ZIC基因还没有被很好地理解。我们已经获得了令人兴奋的初步证据，zic 2和zic 5 调节wntl的转录，wntl是在背侧脑形成期间具有重要功能的基因， 信号传导反过来调节ZIC的转录。这些数据使我们提出WHT和ZIC基因是 参与了一个调节反馈回路。这个新的假设至少可以解释一些缺陷 在ZIC突变体中观察到，并将在不同的模型系统斑马鱼中进行测试。斑马鱼胚胎 在大脑发育的所有阶段都可用，易于观察和操作，并且具有短的 世代时间因此，建立了强有力的遗传学、基因组学和胚胎学方法 用于这种模式生物。zic基因家族的强进化保守性确保了这一点， 这项研究将揭示所有脊椎动物大脑形成过程中共同的分子机制， 包括人类最终，这项工作将有助于更好地了解 影响脊椎动物大脑胚胎发育的潜在出生缺陷。

The staggering functional and anatomical complexity of the vertebrate brain arises gradually during embryonic development from an initially uniform field of cells. We would like to understand the early steps of brain development, in particular, formation of asymmetry along the dorsal/ventral axis of the brain primordium. This study will address the roles of two related transcription factors, zic2 and zic5, during dorsal brain formation. Important functions for both genes have already been demonstrated in several vertebrates, but their mechanisms are not understood. In humans, mutations in zic2 and zic5 have been causally linked to two prevalent birth defects: exencephaly and holoprosencephaly. Expression of zic genes is restricted to the dorsal portion of the neural tube, and this restriction is critical for their correct function. In spite of their obvious importance, the molecular mechanisms of regulation and function of vertebrate zic genes are not well understood. We have obtained exciting preliminary evidence that zic2 and zic5 regulate transcription of wntl, a gene with essential functions during dorsal brain formation, and that Wnt signaling in turn regulates transcription of zics. These data have led us to propose that wht and zic genes are involved in a regulatory feedback loop. This novel hypothesis will help explain at least some of the defects observed in zic mutants, and will be tested in a different model system, the zebrafish. Zebrafish embryos are available during all stages of brain development, are easy to observe and manipulate, and have a short generation time. As a result, powerful genetic, genomic and embryological methods have been established for use in this model organism. Strong evolutionary conservation of the zic gene family ensures that this study will uncover shared molecular mechanisms that operate during brain formation in all vertebrates, including humans. Ultimately, this work will contribute to a better understanding of the mechanisms underlying birth defects that affect embryonic development of the vetebrate brain.