Examining the function of biological sex specific genes: the NLGN4s

摘要 已知NLGNs在突触发生和突触后密度的成熟过程中起关键作用。 通过与支架蛋白、神经递质受体和离子的招募和相互作用 频道。已有研究表明，NRXN结合对NLGN的功能至关重要，因为NRXN能够 在突触后密度(PSD)聚集NLGNs并启动下游相互作用的招募 突触稳定和成熟所必需的蛋白质。大多数脊椎动物都有四个NLGN基因： NLGN1、NLGN2、NLGN3和NLGN4。在大多数哺乳动物中，NLGN4位于X染色体上， 然而，在更高级的灵长类动物中，如智人和泛轮虫，NLGN4X是互补的 在Y染色体(有时称为NLGN5)上，与NLGN4X有近98%的同源性。它是 认为这种NLGN4Y亚型起源于最近发生的复制事件 与几乎所有脊椎动物不同，在进化过程中，人类拥有X染色体和Y染色体 NLGN4的亚型，但NLGN4在突触中的功能仍不清楚。我们打算 研究NLGN4X和NLGN4Y的功能特性，如NRXN结合、突触发生、 和本地化。 我们计划以以下三个具体目标来解决这些问题：1)确定 NLGN4X和NLGN4Y是否定位于人类突触部位。2)确定 NRXN的NLGN4X和NLGN4Y。3)确定分子机制 NLGN4X和NLGN4Y突触生成活性的差异。我们已经进行了实验，以 证明我们能够实现我们提出的三个雄心勃勃的目标中的每一个。对于特定的 目的1、建立研究NLGN在人脑组织和细胞中功能的方法。对于特定的 目的：建立NLGN4亲和力测定方法，并进行实验研究。 生物性别特定的组合。对于特定的目标3，我们已经开始使用突触进行实验 检测系统并表达了NLGN4X和NLGN4Y并产生了开始结构功能的构建体 分析。这些初步数据表明，我们准备在以下方面取得快速进展 对这些性二态基因的理解。结果可能会揭示突触的问题 ASD和学习障碍等障碍的功能障碍，并提出了潜在的差异 男性和女性之间的突触功能。

Abstract NLGNs are known to play crucial roles in synaptogenesis and the maturation of the postsynaptic density through recruitment of and interactions with scaffolding proteins, neurotransmitter receptors, and ion channels. It has been shown that NRXN binding is crucial for NLGN function, as NRXN is capable of clustering NLGNs at the postsynaptic density (PSD) and initiating recruitment of downstream interacting proteins necessary for synapse stabilization and maturation. Most vertebrates possess four NLGN genes: NLGN1, NLGN2, NLGN3, and NLGN4. In most mammals, NLGN4 is located on the X chromosome, however in higher order primates such as Homo sapiens and Pan troglodytes NLGN4X is complemented on the Y chromosome (sometimes referred to as NLGN5) with nearly 98% homology to NLGN4X. It is believed that this NLGN4Y isoform originated from a duplication event that occurred relatively recently during evolution Unlike almost all vertebrates, humans possess X chromosome and Y chromosome isoforms of NLGN4, however the function of NLGN4 at synapses remains unknown. We intend to investigate the functional properties of NLGN4X and NLGN4Y such as NRXN binding, synaptogenesis, and localization. We plan on addressing these questions with the following three specific aims: 1) Determine whether NLGN4X and NLGN4Y are localized to human synaptic sites. 2) Determine the affinities of NLGN4X and NLGN4Y for NRXN. 3) Determine the molecular mechanism responsible for differences in the synaptogenic activity of NLGN4X and NLGN4Y. We have conducted experiments to demonstrate that we can achieve the goals of each of the three ambitious aims we proposed. For specific aim 1, we established approaches to study NLGN function in human brain tissue and cells. For Specific aim 2, we have established an assay and begun experiments to determine the affinity of NLGN4 in biological sex-specific combinations. For specific aim 3, we have begun experiments using a synapse assay system and expressed NLGN4X and NLGN4Y and generated constructs to begin structure function analysis. Together these preliminary data indicate that we are poised to make rapid progress on our understanding of these sexually dimorphic genes. Results are likely to shed light on the matter of synaptic dysfunction in disorders such as ASD and learning disabilities and propose a potential difference in synaptic function between males and females.