Cell-specific survival motor neuron gene expression during human development of the central nervous system: implications for the pathogenesis of spinal muscular atrophy

Abstract

Spinal muscular atrophy is an autosomal recessive disorder characterized by the progressive loss or degeneration of the motor neurons. To investigate the expression of survival motor neuron (SMN), the spinal muscular atrophy-determining gene, and its relationship with the pathogenesis of the disease, we analyzed by means of in situ hybridization the location of SMN mRNA in fetal, newborn, infant, and adult human central nervous system tissues. The large motor neurons of the spinal cord are the main cells that express SMN together with the neurons of the medulla oblongata, the pyramidal cells of the cortex, and the Purkinje cells of the cerebellum. Some sensory neurons from the posterior horn and dorsal root ganglia express SMN to a lesser degree. Furthermore, strong SMN expression is detected in the ependymal cells of the central canal. The expression is present in the spinal cord at 8 weeks of fetal life throughout postnatal and adult life. The sharp expression of SMN in the motor neurons of the human spinal cord, the target cells in spinal muscular atrophy, suggests that this gene is implicated in neuronal development and in the pathogenesis of the disease. The location of the SMN gene expression in other neuronal structures not clearly or directly associated with clinical manifestations or pathological findings of spinal muscular atrophy may indicate a varying sensitivity to the absence or dysfunction of the SMN gene in motor neurons.

Figure 1.

Expression of the SMN gene in fetal spinal cord. A to C: Spinal cord at 8 weeks of development. A: Untreated section, bright field. The cells from the neural epithelium migrate toward the posterior horn and, to a lesser degree, toward the anterior horn. B: Antisense probe, dark field, showing the diffuse expression in the neural epithelium following the pattern of migration of the neural cells into the two horns. C: Sense probe, dark field. Hematoxylin and eosin; (×100). D to F: Dorsal root ganglia at 12 weeks of development. D: Antisense probe, bright field. E: Antisense probe, dark field. F: Sense probe, dark field. Hematoxylin and eosin (×200). G to I: Anterior horn of the spinal cord at 17 weeks of development showing a large expression in neuroblasts. G: Antisense probe, bright field. TB (×400). H: Antisense probe, dark field. TB (×200). I: Sense probe. Hematoxylin and eosin (×200).

Figure 2.

Expression of the SMN gene in adult spinal cord. A to C: Anterior horn. A: Antisense probe, bright field; strong expression in the motor neurons. B: Antisense probe, dark field. C: Sense probe. TB (×200). D: Higher magnification of one of the motor neurons from A. TB (×800). E and F: Expression in small neurons of the posterior horn. E: Antisense probe, bright field. F: Sense probe, bright field. TB (×800). G to I: Cells of the central canal expressing high level of SMN transcript. G: Antisense probe, bright field. H: Antisense probe, dark field. I: Sense probe, dark field. TB (×200).

Figure 3.

Expression of the SMN gene in adult brain cortex, medulla oblongata, and cerebellum. A to C: Neurons of the parietal cerebral cortex expressing SMN transcript mainly in the pyramidal cells of the infragranular layer. A: Antisense probe, bright field. B: Antisense probe, dark field. C: Sense probe, dark field. TB (×200). D to F: Neurons of the medulla oblongata at the level of the olive showing high level of expression. D: Antisense probe, bright field. E: Antisense probe, dark field. F: Sense probe, dark field. TB (×200). G to I: Adult cerebellum with Purkinje cells being the main cell type that expresses SMN. G: Antisense probe, bright field. Arrow: Purkinje cell. TB (×400). H: Antisense probe, dark field. I: Sense probe, dark field. TB (×200).