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的功能和解剖复杂性在胚胎发育期间从最初均匀的细胞区域逐渐产生。我们想了解大脑发育的早期阶段，特别是沿着脑原基的背腹轴沿着不对称的形成。本研究将探讨两个相关转录因子zic 2和zic 5在背侧脑形成过程中的作用。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，zic2和zic5的突变与两种常见的出生缺陷有因果关系：露脑畸形和前脑无裂畸形。zic基因的表达被限制在神经管的背侧部分，并且这种限制对于它们的正确功能是至关重要的。尽管它们具有明显的重要性，但脊椎动物zic基因的调节和功能的分子机制尚未得到很好的理解。我们已经获得了令人兴奋的初步证据，zic2和zic5调节wnt 1的转录，wnt 1是一个在背侧脑形成过程中具有重要功能的基因，而Wnt信号反过来又调节zics的转录。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。这一新的假设将有助于解释至少在zic突变体中观察到的一些缺陷，并将在另一个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是可用的，易于观察和操作，并且世代时间短。因此，强大的遗传学，基因组学和胚胎学方法已建立用于这种模式生物。zic基因家族在进化上的高度保守性确保了这项研究将揭示所有脊椎动物（包括人类）大脑形成过程中共同的分子机制。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出生缺陷机制。

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.