Type I bone morphogenetic protein receptors are expressed on cerebellar granular neurons and a constitutively active form of the type IA receptor induces cerebellar abnormalities

Abstract

Cerebellar granular neurons are the most abundant neuronal type in the CNS. Their number and experimental accessibility have made these neurons a valuable model for investigating mechanisms of cell proliferation and differentiation in the CNS. Proliferation of granular neurons is regulated, at least in part, by the secreted protein Sonic Hedgehog, whereas induction and differentiation both appear to be controlled by bone morphogenetic protein (BMP) signaling. Given the role of BMPs in granular cell differentiation, we postulated that BMP receptors (BMPRs) would be expressed on cerebellar granular neurons and that signaling through these receptors is required for normal differentiation. We found that both BMPRIA and BMPRIB are expressed on granular neuron precursors and on mature granular neurons in the developing cerebellum. To determine if these receptors are sufficient for granular cell induction and/or differentiation in vivo, we introduced a constitutively active BMPRIA construct into the developing cerebellum. The resulting cerebelli showed a simplified folial pattern and ectopic collections of small cells located deep in the cerebellar white matter. Phenotypic analysis demonstrated that the ectopic cells are granular neurons. From these data we suggest that signaling through the type I BMPRs occurs during normal cerebellar development and ectopic activation of this pathway affects normal granular neuron development. Furthermore, the similarity of the cerebellar anomalies arising from perturbed BMPR signaling to human cerebellar malformations suggests that dysregulation of BMP signaling may play a pathogenic role in some human cerebellar abnormalities.