Abstract
Mutations in SLIT and NTRK-like family member 1 (SLITRK1) result in Tourette syndrome (TS). Patients with TS exhibit delayed bone maturation and increased fracture risk. To understand the role of SLITRK1 in bone homeostasis, we examined the skeletal phenotype of Slitrk1 null mice and investigated the mechanisms responsible for altered bone cell function. Slitrk1 null mice had thinner cortical bones due to decreased periosteal bone formation, while trabecular bone density remained unchanged. Slitrk1 was expressed within osteoblast-lineage cells. Consequently, deletion of Slitrk1 in osteoblasts impaired ex vivo differentiation capacity. Loss of SLITRK1 in osteoblast cells reduced levels of TAZ, a RUNX2 co-activator necessary for osteoblast differentiation. These findings provide evidence for a cell-autonomous role of SLITRK1 in periosteal osteoblasts regulating cortical bone homeostasis. Our data further demonstrate that periosteal-, endosteal-, and trabecular-bone homeostasis are controlled by different mechanisms and provide new insight into the skeletal manifestations of TS.