Differential modulation of Sonic-hedgehog-induced cerebellar granule cell precursor proliferation by the IGF signaling network.

The molecular mechanisms regulating organ growth and size remain unclear. Sonic hedgehog (SHH) signaling is a major player in the regulation of cerebellar development: SHH is secreted by Purkinje neurons and acts on the proliferation of granule cell precursors (GCPs) in the external germinal layer. These then become postmitotic and form the internal granular layer but do so in the presence of SHH ligand, begging the question of how the proliferative response to SHH signaling is downregulated in differentiating GCPs. Here, we have determined the precise cellular localization of the expression of insulin-like growth factor (IGF) network components in the developing mouse cerebellum and show that this network modulates the proliferative effects of SHH signaling on GCPs. IGF1 and IGF2 are potent mitogens for GCPs and both synergize with SHH in inducing GCP proliferation. Whereas the proliferative activity of IGF1 or IGF2 on GCPs does not require intact SHH signaling, aspects of SHH activity on GCP proliferation require signaling through the IGF receptor 1. Moreover, we find that 3 of the IGF-binding proteins, IGFBP2, IGFBP3 and IGFBP5, inhibit IGF1/2-induced cell proliferation, whereas IGFBP5 also inhibits SHH-induced GCPs proliferation. This novel function of IGFBP5 that we have uncovered demonstrates the exquisite regulation of SHH signaling by different components of the IGF network.