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NeuroD (ND) is a basic helix-loop-helix transcription factor important for neuronal development and survival. By using a yeast two-hybrid screen, we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2), both of which are known to interact with huntingtin (Htt). Htt is a ubiquitous protein important for neuronal transcription, development, and survival, and loss of its function has been implicated in the pathogenesis of Huntington's disease, a neurodegenerative disorder. However, the mechanism by which Htt exerts its neuron-specific function at the molecular level is unknown. Here we report that Htt interacts with ND via HAP1, and that MLK2 phosphorylates and stimulates the activity of ND. Furthermore, we show that Htt and HAP1 facilitate the activation of ND by MLK2. To our knowledge, ND is the first example of a neuron-specific transcription factor involved in neuronal development and survival whose activity is modulated by Htt. We propose that Htt, together with HAP1, may function as a scaffold for the activation of ND by MLK2.
Fig. 4. Htt, HAP1, and MLK2 activate ND. (A) Xenopus embryos were injected in one blastomere at the two-cell stage with various combinations of mRNA as indicated. Formation of ectopic neurons induced by ND was visualized as dark staining at the tail-bud stage by whole-mount immunostaining with an antibody against the neuronal marker N-CAM. A limiting amount of ND mRNA was used to elicit a minimal neurogenic response when injected alone (indicated by the arrow, Left Center). Results shown are representative of at least three independent experiments. (B) Quantitation of ectopic neurogenesis induced by ND. Bar graph shows mean percent of Xenopus embryos with ectopic neurons ± SEM of at least three independent experiments performed as described above. Dark areas show mean percent of Xenopus embryos with extensive and intense ectopic neurogenesis.
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