2 research outputs found
Loss of Fgfr1 and Fgfr2 in Scleraxis-lineage cells leads to enlarged bone eminences and attachment cell death
BACKGROUND
Tendons and ligaments attach to bone are essential for joint mobility and stability in vertebrates. Tendon and ligament attachments (ie, entheses) are found at bony protrusions (ie, eminences), and the shape and size of these protrusions depend on both mechanical forces and cellular cues during growth. Tendon eminences also contribute to mechanical leverage for skeletal muscle. Fibroblast growth factor receptor (FGFR) signaling plays a critical role in bone development, and Fgfr1 and Fgfr2 are highly expressed in the perichondrium and periosteum of bone where entheses can be found.
RESULTS AND CONCLUSIONS
We used transgenic mice for combinatorial knockout of Fgfr1 and/or Fgfr2 in tendon/attachment progenitors (ScxCre) and measured eminence size and shape. Conditional deletion of both, but not individual, Fgfr1 and Fgfr2 in Scx progenitors led to enlarged eminences in the postnatal skeleton and shortening of long bones. In addition, Fgfr1/Fgfr2 double conditional knockout mice had more variation collagen fibril size in tendon, decreased tibial slope, and increased cell death at ligament attachments. These findings identify a role for FGFR signaling in regulating growth and maintenance of tendon/ligament attachments and the size and shape of bony eminences
Identifying vulnerable brain networks in mouse models of genetic risk factors for late onset Alzheimer's disease
The major genetic risk for late onset Alzheimer’s disease has been associated with the presence of APOE4 alleles. However, the impact of different APOE alleles on the brain aging trajectory, and how they interact with the brain local environment in a sex specific manner is not entirely clear. We sought to identify vulnerable brain circuits in novel mouse models with homozygous targeted replacement of the mouse ApoE gene with either human APOE3 or APOE4 gene alleles. These genes are expressed in mice that also model the human immune response to age and disease-associated challenges by expressing the human NOS2 gene in place of the mouse mNos2 gene. These mice had impaired learning and memory when assessed with the Morris water maze (MWM) and novel object recognition (NOR) tests. Ex vivo MRI-DTI analyses revealed global and local atrophy, and areas of reduced fractional anisotropy (FA). Using tensor network principal component analyses for structural connectomes, we inferred the pairwise connections which best separate APOE4 from APOE3 carriers. These involved primarily interhemispheric connections among regions of olfactory areas, the hippocampus, and the cerebellum. Our results also suggest that pairwise connections may be subdivided and clustered spatially to reveal local changes on a finer scale. These analyses revealed not just genotype, but also sex specific differences. Identifying vulnerable networks may provide targets for interventions, and a means to stratify patients