Stabilization of Dll1 mRNA by Elavl1/HuR in neuroepithelial cells undergoing mitosis

摘要

In the vertebrate neuroepithelium, the decision to differentiate is made by neural precursors soon after mitosis, when they are apically located. This process is controlled by lateral inhibitory signals triggered by the Delta/Notch pathway. During mitosis, the capacity of neural precursors to express the neurogenic genes Dll1 and Notch1 is maximal due to mRNA stabilization, but the mechanism controlling this process remains unknown. Here we show that Elav-like (Elavl1)/HuR becomes enriched in the cytoplasm of neuroepithelial cells undergoing mitosis and that this ribonucleoprotein interacts with the 3′ untranslated region (UTR) of Dll1 mRNA. This interaction is functionally relevant because RNAi against Elavl1 reduces the stability of Dll1– 3′UTR-containing transcripts in mitosis-arrested neuroepithelial cells, and Elavl1 null-mutant heterozygous mice show decreased Dll1 expression in the developing brain in vivo. We also show that RNAi against Elavl1 diminishes the capacity of brain precursors to trigger lateral inhibitory signals to their neighbors, an observation consistent with the increase in the rate of neurogenesis which can be detected in vivo in the developing retina of Elavl1 heterozygous mice. We conclude that Elavl1/HuR facilitates the exposure of vertebrate neuronal precursors to apically located Delta/Notch signals.