Developmental Regulation of Brain and Behavior

描述(申请人提供)：建议的研究将阐明五个基因及其蛋白质产物在大脑和行为发育中的作用。他们专注于斑马雀前脑中歌曲控制系统的结构和功能的性别分化。只有男性唱歌，而男性控制歌唱的大脑区域要大得多，这是因为男性在这些区域比女性有更多和更大的细胞。在许多脊椎动物中，这些类型的偏向男性的行为和形态差异的发展主要受性腺类固醇的调节。然而，在一些哺乳动物系统中，性别分化更直接地受到基因表达的控制。在斑马雀身上，证据表明两者都参与其中。目前的提案将检验这一假设，即斑马雀鸣叫系统的雄性化由基因控制，包括Z染色体上的基因(与XX/XY哺乳动物不同，雄性斑雀是ZZ，雌性是ZW)，这些基因影响大脑对类固醇激素的反应。这项工作涉及我们最近在斑马雀大脑中发现的五个基因的特征，与女性相比，这些基因在雄性斑马雀的歌曲控制核团中的表达增强。这些基因包括编码核糖体蛋白L17和L37的基因、分泌载体膜蛋白1(SCAMP1)、锌指蛋白216(ZNF216)和含有COBW结构域的蛋白。我们将完成这些基因的序列分析，确定它们在斑马雀染色体上的位置，并确定它们在鸣叫回路和相关区域内性别二态表达的时间进程。抑制它们的功能对歌曲学习的发展和歌曲系统形态的男性化的影响将被阐明。此外，还将研究这些基因和类固醇激素之间的相互作用。例如，将研究雌激素在基因表达中的作用以及与雄激素受体的潜在相互作用，这两个因素都涉及男性化。关于这些基因的文献信息非常少，因此随着这项工作的进行，我们不仅将了解更多关于性别分化的调节机制，而且还将了解这些基因本身。然而，最重要的是，拟议的研究将阐明对大脑结构和功能正常发展至关重要的机制，并可能导致发现问题的解决方案，包括与疾病、损伤、衰老和污染物暴露相关的问题。

DESCRIPTION (provided by applicant): The proposed studies will elucidate the roles of five genes and their protein products in the development of brain and behavior. They focus on sexual differentiation of the structure and function of the song control system in the forebrain of zebra finches. Only males sing, and the brain areas that control song are far larger in males, which is due to males having more and larger cells in these regions than females. In many vertebrates, the development of these types of male-biased differences in behavior and morphology is regulated mainly by gonadal steroids. However, in some mammalian systems, sexual differentiation is controlled more directly by the expression of genes. In zebra finches, the evidence suggests that both are involved. The present proposal will test the hypothesis that masculinization of the zebra finch song system is controlled by genes, including those on the Z-chromosome (unlike XX/XY mammals, male zebra finches are ZZ and females are ZW), that influence the response of the brain to steroid hormones. The work involves characterization of five genes we recently identified in the zebra finch brain with enhanced expression in song control nuclei in males compared to females. These genes include those encoding ribosomal proteins L17 and L37, secretory carrier membrane protein 1 (SCAMP1), zinc finger protein 216 (ZNF216) and a COBW-domain containing protein. We will complete the sequence analysis for these genes, confirm their locations on zebra finch chromosomes, and determine the time-course of their sexually dimorphic expression within the song circuit and related regions. The effects of inhibiting their function on development of song learning and masculinization of song system morphology will be elucidated. In addition, interactions between the genes and steroid hormone will be investigated. For example, the role of estradiol in the expression of the genes and potential interactions with androgen receptors, both of which are involved in masculinization, will be studied. Very little information is available in the literature on these genes, so as this work is pursued, we will learn not only more about mechanisms regulating sexual differentiation, but also about the genes themselves. Most importantly, however, the proposed studies will elucidate mechanisms critical for normal development of brain structure and function, and can lead to the discovery of solutions to problems, including those associated with disease, injury, aging and contaminant exposure.