Indicative oligodendrocyte dysfunction in spinal cords of human fetuses suffering from a lethal motoneuron disease

Abstract

Human spinal cord development is still poorly understood and detailed molecular analyses of human motoneuron diseases could improve our understanding of the normal developmental processes of the spinal cord. Lethal Congenital Contracture Syndrome (LCCS, MIM 253310) provides a human model to study the early motoneuronal development. A typical phenotype of LCCS fetuses consists of multiple joint contractures, distinct facial features, and hydrops. Tissue pathology is characterized by severe muscle atrophy, lung hypoplasia, and degeneration of the anterior horn of the spinal cord as the hallmark of the syndrome. In this study we performed a global transcript analysis of LCCS spinal cords. The RNA expression profiles of these spinal cords were compared to age-matched healthy control fetuses, aborted for nonrelated causes. In addition, we applied phylogenetic footprinting methods to decipher the mechanisms of transcriptional regulation in the affected transcripts. Changes in transcripts involved with the development of the CNS and oligodendrocytes were obvious and the transcription factor PAX6 was identified as a key regulator during spinal cord development. In addition, transcript pathway analysis clearly indicated genes belonging to groups with neuronal functions to be affected. Our findings support the hypothesis that human motoneurons and oligodendrocytes are dependent on each other during their development and are influenced by distinct transcription factors previously known to act during murine and chick motoneuron development. These data provide valuable information about the molecular pathways putatively active in motoneuron diseases.