Role for zic genes in the developing midbrain.

脊椎动物大脑令人震惊的功能和解剖复杂性在 胚胎从最初均匀的细胞场发育而来。我们想要了解一下 大脑发育，尤其是沿大脑背轴/腹轴形成的不对称性 原基植物。这项研究将探讨两个相关的转录因子zic2和zic5在背部的作用。 大脑的形成。这两个基因的重要功能已经在几种脊椎动物中得到证实， 但人们并不了解它们的机制。在人类中，zic2和zic5的突变是有因果关系的。 两种常见的出生缺陷：外脑畸形和全前脑畸形。Zic基因的表达仅限于 神经管的背部，这一限制对它们的正常功能至关重要。 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振奋的初步证据，zic2和zic5 调节在背侧脑形成过程中具有重要功能基因wnt1的转录，以及wnt1 信号转而调节ZIC的转录。这些数据使我们提出Wht和zic基因是 卷入了一个监管反馈循环。这一新颖的假说将有助于解释至少部分缺陷。 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。斑马鱼的胚胎是 适用于大脑发育的所有阶段，易于观察和操作，并具有短暂的 世代时间。因此，建立了强大的遗传、基因组和胚胎学方法。 在这个模式生物中使用。Zic基因家族强大的进化保守性确保了这一点 这项研究将揭示所有脊椎动物在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理解这些机制 影响脊椎动物大脑胚胎发育的潜在先天缺陷。

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.