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。之前对FREM3的研究表明，它可能在为人类大脑皮层的脑细胞提供结构性支持方面发挥作用。然而，FREM3在人的一生中对大脑皮质形状和结构的特定方面的确切影响仍然不完全清楚。我们最近发现，FREM3在人类前额叶皮质的表达随着年龄的增长而下降，这是一个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表达降低相关的遗传变异与同一区域皮质活动减少以及认知能力下降有关。尽管这些初步发现是有希望的，但它们几乎没有提供对可能构成这些广泛影响的潜在细胞机制的洞察。此外，它们仅限于年轻人，不能告诉我们太多关于这种强烈依赖年龄的基因如何影响大脑结构和功能在整个生命周期中变化的轨迹。最后，这些结果依赖于FREM3基因表达的自然个体差异与大脑结构/功能之间的相关性，而不能证明两者之间存在因果联系。为了填补这些重要的空白，我们建议研究FREM3及其小鼠同源物Frem3在自然发生和实验诱导的表达中的变异性，以详细衡量皮质形态和整个寿命的认知。拟议的工作将围绕三个主要目标组织：目标1：评估以常见功能基因变体为索引的自然发生的FREM3表达变异性对磁共振成像得出的人类皮质结构和认知在整个寿命内的详细测量的影响。目的2：在正常衰老的小鼠模型中，确定Frem3基因表达的寿命轨迹、皮质结构和认知变化之间的联系。目的3：评估实验诱导的FREM3在小鼠模型中的破坏如何影响大脑皮质结构和认知变化的寿命轨迹。该项目旨在为目前功能不佳的FREM3基因的功能提供重要的洞察力。鉴于该基因与发育、衰老和精神病理学的关联，解开其不同功能背后的分子途径可以提高我们对大脑结构和一生中功能的基本理解。

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.