Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma

A communication system in cells called the Hedgehog signaling pathway plays an essential role in the formation of tissues and organs in animal embryos. The activity of the pathway is carefully controlled during development and if Hedgehog signaling is disrupted it can lead to developmental defects and particular types of cancer. Some of these cancers can be treated with a drug called vismodegib, which targets a particular molecule in the Hedgehog signaling pathway. However, tumor cells can become resistant to this drug, so researchers are hoping to find new therapies that target other aspects of the signaling pathway. Hedgehog signaling promotes the division of brain cells called granule neuron precursor cells (or GNP cells for short). If the signaling pathway is over-active it can trigger the GNP cells to divide more than they should. This can lead to medulloblastoma, which is the most common type of brain tumor that affects children. Proteins called Neuropilins—which bind to molecules known as Semaphorins—promote Hedgehog signaling and the formation of medulloblastoma, but it was not clear how this works. Here Ge et al. studied the role of Neuropilin in cultured cells and in the cerebellum of mice. The experiments show that Semaphorin 3 promotes the accumulation of an enzyme called PDE4D at the cell membrane. PDE4D interacts with Neuropilin and blocks the activity of another enzyme that normally inhibits Hedgehog signaling. In mice that lack Neuropilin and Semophorin 3, the GNP cells are less able to divide, which leads to abnormal development of the cerebellum. Further experiments show that drugs that target PDE4D inhibit both the Hedgehog pathway and the growth of tumors that are resistant to vismodegib treatment. Ge et al.'s findings uncover a new way in which Hedgehog signaling is regulated and highlight a potential new strategy for treating medulloblastoma and other similar tumors. Current PDE4D inhibitors are associated with severe side effects, so the next challenge is to develop new drugs that have fewer side effects.