Left-Right Asymmetry of the Developing Diencephalon

人们早就知道，人脑的左半球和右半球在解剖学上是不同的， 功能上不同，但皮质不对称是如何产生的，或在神经系统疾病中受到干扰， 是很难理解的。相比之下，在解开分子机制方面已经取得了重大进展。 内脏器官不对称发育的遗传基础。Nodal信号通路的组分， 在调节内脏不对称性的功能，也特别表达在左侧的 正在发育的斑马鱼大脑这种短暂的左侧基因表达定位于松果体器官原基。 缺乏不对称基因表达的鱼后来显示出基因组左右定位的随机性。 成熟松果体的柄。低等脊椎动物间脑的其他不对称包括 左侧松果体旁器和左侧缰核与右侧缰核之间的形态学差异。 这项建议的总体目标是确定如何间脑不对称出现在斑马鱼 个脑袋在AIM I中，将使用转基因斑马鱼实时监测松果体发育。初步 数据表明，松果体旁起源于松果体原基。命运映射将解决细胞 直接从会阴旁开始松果体旁似乎影响邻近背侧的转录 缰，在缰基因表达中产生左右差异。在AIM II中，一个合作实验室项目 将导致在幼虫间脑中发现新的分子不对称性。的假设 将通过检查缰核的表达来测试松果体旁调节缰核的偏侧性。 标记物在突变体与改变左右图案，或以下选择性消融的会阴旁。在 AIM III，一个集中的遗传筛选将确定新的ENU诱导的突变，影响形成 间脑不对称在试点筛选中分离的两个突变，失去了缰不对称性， 在AIM IV中进一步表征，总之，拟议的实验将提供更好的理解 脊椎动物前脑左右特化的遗传机制。

It has long been known that the left and right hemispheres of the human brain are anatomically and functionally different, yet how cortical asymmetries are generated, or perturbed in neurological disorders, is poorly understood. In contrast, significant progress has been made towards unraveling the molecular genetic basis for asymmetric development of visceral organs. Components of the Nodal signaling pathway, that function in regulating visceral asymmetry, are also specifically expressed on the left side of the developing zebrafish brain. This transient, left-sided gene expression localizes to the pineal organ anlage. Fish lacking asymmetric gene expression later show a randomization in the left-right positioning of the stalk of the mature pineal gland. Other asymmetries in the diencephalon of lower vertebrates include the left-sided parapineal organ and morphological differences between the left and fight habenular nuclei. The overall goal of this proposal is to determine how diencephalic asymmetries arise in the zebra fish brain. In AIM I, pineal development will be monitored real-time using transgenic zebrafish. Preliminary data suggest that the parapineal is derived from the pineal anlage. Fate mapping will address the cellular origin of the parapineal directly. The parapineal appears to influence transcription in the adjacent dorsal habenula, creating a left-right difference in habenular gene expression. In AIM II, a collaboratory project will lead to the discovery of new molecular asymmetries in the larval diencephalon. The hypothesis that the parapineal regulates the laterality of the habenulae will be tested by examining expression of habenular markers in mutants with altered left-right patterning, or following selective ablation of the parapineal. In AIM III, a focused genetic screen will identify new ENU-induced mutations that affect the formation of diencephalic asymmetries. Two mutations isolated in a pilot screen that lose habenular asymmetry will be characterized further in AIM IV, Together, the proposed experiments will provide a greater understanding of the genetic mechanisms that underlie left-right specialization of the vertebrate forebrain.