Behavioural effects of extracellular matrix protein Fras1 depletion in the mouse

Abstract

Fras1 is an extracellular protein of the basement membranes that surround embryonic epithelia, choroid plexuses and meninges in foetal mouse brain. Depletion of Fras1 in knockout mice results in sub-epidermal blistering and fusion of eyelids and digits as well as malformation of lungs and kidneys. Mutations in the human counterpart FRAS1 are responsible for the Fraser Syndrome with clinical manifestations similar to the murine phenotype. In addition, brain deformities or mental impairments have occasionally been reported in patients with Fraser Syndrome. In the present study, we explored the possible involvement of Fras1 in brain function, analysing its expression pattern in mouse brain and investigating aspects of Fras1 −/− mice behaviour, related to the function of brain regions expressing Fras1. Transcripts were detected in choroid plexuses and in certain brain regions including cortical, hippocampal and amygdalar areas in juvenile mice. Behavioural tests revealed that Fras1 −/− mice exhibit impaired egocentric spatial memory, aberrant olfactory learning and memory, markedly reduced fear memory in an auditory fear conditioning task, as well as reduced anxiety expression in open field and elevated plus maze tests. Moreover, the extracellular matrix organization has been severely affected in cortical and subcortical areas as demonstrated by Wisteria floribunda agglutinin immunolabelling. The widespread detection of Fras1 transcripts in the brain of both pre-and postnatal mice, as well as the behavioural and cellular disturbances exhibited by Fras1 −/− adult mice provide evidence for the involvement of Fras1 in brain organization and function.

Brain extracellular matrix: An upcoming target in neurological and psychiatric disorders

“…They provide insights into the interplay between the major ECM proteins and the intracellular Tau levels, and demonstrate a direct effect of aggrecan on Tau expression and phosphorylation. Kalpachidou et al (2020) describe the behavioral phenotype of mice deficient in Fras1, an extracellular protein of the basement membranes that surround embryonic epithelia, choroid plexuses and meninges in fetal mouse brain. Mutations in human Fras1 are responsible for the Fraser Syndrome with brain deformities and mental impairments occasionally observed in patients.…”

“…Kalpachidou et al. (2020) describe the behavioral phenotype of mice deficient in Fras1, an extracellular protein of the basement membranes that surround embryonic epithelia, choroid plexuses and meninges in fetal mouse brain. Mutations in human Fras1 are responsible for the Fraser Syndrome with brain deformities and mental impairments occasionally observed in patients.…”

Blood and brain transcriptome analysis reveals APOE genotype-mediated and immune-related pathways involved in Alzheimer disease

“…Additionally, HLA-DQA1 and INPP5D are expressed in dendritic cells and monocytes and involved in immune processes, and the migration of monocytes across an inflamed BBB can cause differentiation into dendritic cells [47]. FRAS1 was significantly downregulated in AD compared to controls in blood from ε3/ε4 AD individuals and a recent study showed that FRAS1 knockdown mice were impaired in memory and learning behaviors [48].…”

Blood and Brain Transcriptome Analysis Reveals APOE Genotype-mediated and Immune-related Pathways Involved in Alzheimer Disease

“…Additionally, HLA-DQA1 and INPP5D are expressed in dendritic cells and monocytes and involved in immune processes, and the migration of monocytes across an inflamed BBB can cause differentiation into dendritic cells [42]. FRAS1 was significantly downregulated in AD compared to controls in blood from ε3/ε4 AD individuals and a recent study showed that FRAS1 knockdown mice were impaired in memory and learning behaviors [43].…”