No abstract

Mutations in the Hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma, one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our previous study revealed how PDE4D controls global levels of cAMP in the cytoplasm to positively regulate Hh signaling; in the present study we found that a specific isoform PDE4D3 is tethered to the centrosome by myomegalin, a centrosome/Golgi associated protein. Myomegalin loss dislocates PDE4D3 from the centrosome, leading to local PKA over-activation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Myomegalin loss suppresses the proliferation of granule neuron precursors, and blocks the growth of medulloblastoma in mouse model. Our findings specify a new regulatory mechanism of the Hh pathway, and highlight an exciting therapeutic avenue for Hh-related cancers with reduced side effects.

Mutations in the Hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma, one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our previous study revealed how PDE4D controls global levels of cAMP in the cytoplasm to positively regulate Hh signaling; in the present study we found that a specific isoform PDE4D3 is tethered to the centrosome by myomegalin, a centrosome/Golgi associated protein. Myomegalin loss dislocates PDE4D3 from the centrosome, leading to local PKA overactivation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Myomegalin loss suppresses the proliferation of granule neuron precursors, and blocks the growth of medulloblastoma in mouse model. Our findings specify a new regulatory mechanism of the Hh pathway, and highlight an exciting therapeutic avenue for Hh-related cancers with reduced side effects.

Human pluripotent stem cells (hPSCs) frequently become aneuploid with abnormal chromosome numbers due to mitotic chromosome segregation errors during propagation in culture. Yet, we do not understand why hPSCs exhibit a low mitotic fidelity. Here we investigate the mechanisms responsible for mitotic errors in hPSCs and show that the primary cause is lagging chromosomes with improper merotelic chromosome microtubule attachments in anaphase. Accordingly, we can improve merotelic error correction and reduce lagging chromosome rates in hPSCs using small molecules that prolong mitotic duration or destabilize chromosome microtubule attachments providing chemical strategies to preserve genome stability. Strikingly, we also demonstrate that mitotic error rates correlate with developmental potential decreasing upon differentiation and loss of pluripotency and conversely increasing after reprogramming to a pluripotent state. Thus, chromosome segregation fidelity is inherently low in hPSCs and depends on developmental state in normal human cells.