Role for zic genes in the developing midbrain.

描述（由申请人提供）：脊椎动物大脑的惊人功能和解剖学复杂性在胚胎发育过程中逐渐从最初均匀的细胞场中产生。我们想了解大脑发育的早期步骤，特别是沿着大脑原基的背/腹轴形成的不对称。本研究将探讨两个相关转录因子zic2和zic5在背脑形成过程中的作用。这两种基因的重要功能已经在几种脊椎动物中得到证实，但它们的机制尚不清楚。在人类中，zic2和zic5的突变与两种常见的出生缺陷有因果关系：畸形和前脑全裂。zic基因的表达被限制在神经管的背侧部分，这种限制对它们的正确功能至关重要。尽管它们具有明显的重要性，但脊椎动物锌基因的调控和功能的分子机制尚不清楚。我们已经获得了令人兴奋的初步证据，证明zic2和zic5调节wnt1的转录，而Wnt信号反过来调节zics的转录。wnt1是一个在背脑形成过程中具有重要功能的基因。这些数据使我们提出wnt和zic基因参与了一个调节反馈回路。这个新颖的假设将有助于解释至少在锌突变体中观察到的一些缺陷，并将在一个不同的模型系统——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以获得，易于观察和操作，并且世代时间短。因此，已经建立了强大的遗传学、基因组学和胚胎学方法来研究这种模式生物。zic基因家族强大的进化保守性确保了这项研究将揭示包括人类在内的所有脊椎动物在大脑形成过程中共同运作的分子机制。最终，这项工作将有助于更好地理解影响脊椎动物大脑胚胎发育的先天缺陷的潜在机制。

DESCRIPTION (provided by applicant): 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 wnt1, 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 wnt 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 vertebrate brain.