Mutations in the WWOX gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous WWOX mutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of a WWOX-deficient human fetus from this family. A similar disorganization of cortical layers was identified in lde/lde rats (carrying a homozygous truncating mutation which disrupts the active Wwox C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of the WWOX gene in migrating neurons across different species.

Medial meniscus destabilization (MMD) is a surgical insult technique for modeling osteoarthritis (OA) by replicating chronic abnormal cartilage loading in animal joints in vivo. The present study aimed to characterize the immediate biomechanical effects (ex vivo) and short‐term histological consequences (in vivo) of MMD in the rabbit knee. In a compressive loading test, contact stress distribution in the medial compartment was measured in eight cadaver rabbit knees, initially with all major joint structures uninjured (Baseline), after MMD, and finally after total medial meniscectomy (TMM). Similarly, the effects on sagittal joint stability were determined in an anterior–posterior drawer test. These biomechanical (ex vivo) data indicated that both MMD and TMM caused significant (p < 0.001), distinct (>1.5‐fold) elevation of peak local contact stress in the medial compartment, while leaving whole‐joint stability nearly unchanged. Histological consequences in vivo were assessed in a short‐term (8‐week) survival series of MMD or TMM (five animals for each group), and both caused moderate cartilage degeneration in the medial compartment. The MMD insult, which is feasible through posterior arthrotomy alone, is as effective as TMM for modeling injurious‐level chronic abnormal cartilage loading in the rabbit knee medial compartment in vivo, while minimizing potential confounding effects from whole‐joint instability. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1555–1560, 2013.