Expression of Bone Morphogenetic Protein-4 in the Cortical Lesions of Focal Cortical Dysplasia IIb and the Tuberous Sclerosis Complex

Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are malformations of cortical development (MCDs) and are frequently associated with medically intractable epilepsy. Previous studies have indicated that developmental abnormalities during the early stages of cortical development contribute to the onset of these diseases. Bone morphogenetic protein-4 (BMP-4) is a well-documented key regulator of cortical development. To understand the potential roles of BMP-4 in the cortical lesions associated with MCDs, we investigated the expression pattern of BMP-4 in surgical specimens from patients with FCD IIb (n = 8) and TSC (cortical tubers; n = 12), and age-matched normal cortices (CTX) (n = 8) from autopsy samples were used as controls. The immunohistochemical results demonstrated that the overall immunoreactivity of the BMP-4 staining was diminished in the dysplastic cortices of the FCD IIb and TSC samples compared to the CTX samples. Moderate to strong BMP-4 immunoreactivity, however, was observed in malformed neurons, including dysmorphic neurons, giant neurons, balloon cells, giant cells, and reactive astrocytes. The confocal analysis demonstrated that most malformed neurons expressing BMP-4 were co-labeled with neuronal rather than astrocytic markers, indicating a neuronal lineage. Moreover, the decreased BMP-4 expression within the dysplastic cortex was confirmed by western blot analysis. In conclusion, the downregulation and altered cellular distribution of BMP-4 protein observed in MCDs suggests that BMP-4 may be involved in the pathogenesis of abnormal cortical development.