The FREM3 gene and its role in shaping brain morphology and function across the lifespan

最近发现的人类FREM3基因与大脑发育和衰老的生物学有关。先前对FREM3的研究表明，它可能在为人类皮层的脑细胞提供结构支持方面发挥作用。然而，FREM3在人类一生中对大脑皮层形状和结构的特定方面的确切影响尚不完全清楚。我们最近发现，人类前额叶皮层中FREM3的表达随着年龄的增长而下降，前额叶皮层是与认知有关的对年龄敏感的大脑区域。我们进一步表明，与FREM3低表达相关的基因变异与同一区域皮层活动减少以及认知能力下降有关。虽然这些初步发现很有希望，但它们对潜在的细胞机制提供的见解很少，这些机制可能是这些广泛影响的基础。此外，它们仅限于年轻人，无法告诉我们这种强烈的年龄依赖性基因如何在整个生命周期中塑造大脑结构和功能变化的轨迹。最后，这些结果依赖于自然发生的FREM3基因表达和大脑结构/功能的个体差异之间的相关性，不能证明因果关系。为了填补这些重要的空白，我们建议研究自然发生的和实验诱导的FREM3及其小鼠同源物FREM3在整个生命周期中皮层形态和认知的详细测量中的表达变异性。目标1：评估自然发生的FREM3表达变异性的影响，以常见的功能遗传变异为索引，对mri衍生的人类皮层结构和认知的详细测量进行评估。目的2：在正常衰老的小鼠模型中，确定Frem3表达、皮质结构和认知变化的寿命轨迹之间的联系。目的3：评估小鼠模型中实验诱导的Frem3破坏如何影响皮质结构和认知变化的寿命轨迹。该项目旨在为目前尚不清楚的FREM3基因的功能提供重要的见解。考虑到该基因与发育、衰老和精神病理的关联，揭示其多种功能背后的分子途径可以提高我们对整个生命周期的大脑结构和功能的基本理解。

The recently identified human FREM3 gene has been implicated in the biology of brain development and aging. Previous work on FREM3 suggests it may play a role in providing structural support for brain cells in the human cortex. However, the precise effects on FREM3 on specific aspects of the shape and structure of human cortex over the lifespan remain incompletely understood. We recently showed that FREM3 expression in human prefrontal cortex, an age-sensitive brain region implicated in cognition, goes down with aging. We further showed that genetic variants associated with lower FREM3 expression are linked to reduced cortical activity in the same region, as well as reduced cognitive performance. Although these initial findings are promising, they provide little insight into the potential cellular mechanisms that may underlie these broad effects. In addition, they are restricted to young adults and cannot tell us much about how this strongly age-dependent gene may shape trajectories of brain structure and function changes across the lifespan. Finally, these results rely on correlation between naturally occurring individual differences in FREM3 gene expression and brain structure/function and cannot prove a causal link. To fill these important gaps, we propose to study both naturally occurring and experimentally induced variability in the expression of FREM3 and its mouse homologue Frem3 on detailed measures of cortical morphology and cognition across the lifespan. The proposed work will be organized around three main aims: Aim 1: Evaluate the effects of naturally occurring FREM3 expression variability, indexed by common functional genetic variants, on MRI-derived detailed measures of human cortical structure and cognition across the lifespan. Aim 2: Identify links between lifespan trajectories in Frem3 expression, cortical structure and cognitive change in a mouse model of normal aging. Aim 3: Evaluate how experimentally induced disruption of Frem3 in a mouse model affects lifespan trajectories of change in cortical structure and cognition. This project is slated to provide important insight into the function of the currently poorly characterized FREM3 gene. Given the association of this gene with development, aging and psychopathology, unraveling the molecular pathways underlying its diverse functionality can improve our basic understanding of brain structure and function across the lifespan.