Hormonal and Genetic Regulation of Brain Development

描述(申请人提供)：不同种类的脊椎动物雄性和雌性的大脑和行为有所不同。斑马雀鸣叫系统是一个特别有用的模型，用于理解神经结构和功能上的性别差异的调节机制，原因有很多，包括在一个相对简单的神经回路中，雄性和雌性之间存在极大的形态差异，其中大脑区域具有明确的功能。斑马雀基因组的最新测序为获得分子工具和资源提供了新的途径。与哺乳动物物种一样，雌二醇(E2)可以诱导一些男性化，但大量证据表明，额外的分子对正常的男性发育至关重要。我建议测试一个新的、独特的假设，即类固醇激素E2与一个或多个性染色体基因的男性表达水平相一致，以调节适当的男性发育。这项工作将提供关键的新信息，因为关于E2和其他调节性分化的分子之间相互作用的数据在不同物种之间非常有限。这些实验涉及三个基因，我们确定这些基因在发育中的男性比女性的特定歌曲控制核团中表达增加。总而言之，这些研究将提供一个有凝聚力的信息体系，整合调节大脑结构发展的荷尔蒙和遗传因素，以及一种习得的社会行为--语音交流，这是人类使用的主要方式。具体地说，我们将使用分子、细胞、解剖学和行为学方法的组合来测试关于E2和特定分子在前脑结构和功能发育中的关系的假设。这些想法并不是相互排斥的，包括：(1)E2增加分泌载体膜蛋白1(SCAMP1)、微管蛋白特异性伴侣A(TBCA)和/或酪氨酸激酶B(TrkB，脑源性神经营养因子的高亲和力受体)的表达；(2)这些基因和BDNF配体调节男性化，部分是通过增加发育中的大脑对E2的反应性；(3)E_2和基因/蛋白具有互补作用，包括E_2增加BDNF的可利用性，SCAMP1和TbCA定位于促进BDNF的释放，TbCA和TrkB被定位为可增强BDNF的作用能力。

DESCRIPTION (provided by applicant): Brain and behavior differ between males and females across vertebrate species. The zebra finch song system is a particularly useful model for understanding mechanisms that regulate development of sex differences in neural structure and function for many reasons, including extremely large morphological differences between males and females in a relatively simple neural circuit in which brain regions have clearly identified functions. Recent sequencing of the zebra finch genome provides new access to molecular tools and resources. As in mammalian species, estradiol (E2) can induce some masculinization, but a variety of pieces of evidence indicate that additional molecules are critical to normal male development. I propose to test a new, unique hypothesis, that the steroid hormone E2 acts in concert with masculine levels of expression of one or more sex chromosome genes to regulate appropriate male development. This work will provide critical novel information, as data on interactions between E2 and other molecules regulating sexual differentiation are very limited across species. The experiments involve three genes that we determined exhibit increased expression in specific song control nuclei in developing males compared to females. Collectively, the studies will provide a cohesive body of information integrating hormonal and genetic factors regulating development of brain structure and a learned social behavior - vocal communication, the primary modality used by humans. Specifically, we will use combinations of molecular, cellular, anatomical and behavioral approaches to test hypotheses about the relationships among E2 and specific molecules in development of forebrain structure and function. The ideas, which are not mutually exclusive, include that: (1) E2 increases expression of secretory carrier membrane protein 1 (SCAMP1), tubulin specific chaperone A (TBCA) and/or tyrosine kinase B (TrkB, the high affinity receptor for brain derived neurotrophic factor - BDNF); (2) These genes and the BDNF ligand modulate masculinization, in part by increasing responsiveness of the developing brain to E2; and (3) E2 and the genes/proteins can have complementary effects, including that E2 increases availability of BDNF, SCAMP1 and TBCA are positioned to facilitate BDNF's release, and TBCA and TrkB are localized such that they can increase BDNF's ability to act.