Negative regulation of Yap during neuronal differentiation.
Regulated proliferation and cell cycle exit are essential aspects of neurogenesis. The Yap transcriptional coactivator controls proliferation in a variety of tissues during development, and this activity is negatively regulated by kinases in the Hippo signaling pathway. We find that Yap is expressed in mitotic mouse retinal progenitors and it is downregulated during neuronal differentiation. Forced expression of Yap prolongs proliferation in the postnatal mouse retina, whereas inhibition of Yap by RNA interference (RNAi) decreases proliferation and increases differentiation. We show Yap is subject to post-translational inhibition in the retina, and also downregulated at the level of mRNA expression. Using a cell culture model, we find that expression of the proneural basic helix-loop-helix (bHLH) transcription factors Neurog2 or Ascl1 downregulates Yap mRNA levels, and simultaneously inhibits Yap protein via activation of the Lats1 and/or Lats2 kinases. Conversely, overexpression of Yap prevents proneural bHLH proteins from initiating cell cycle exit. We propose that mutual inhibition between proneural bHLH proteins and Yap is an important regulator of proliferation and cell cycle exit during mammalian neurogenesis.
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Huanqing
H
Zhang
Monika
M
Deo
Robert C
RC
Thompson
Michael D
MD
Uhler
David L
DL
Turner
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism*; D034622:RNA Interference; D012160:Retina / Q000166:cytology*; D013234:Stem Cells / Q000378:metabolism; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C499317:Ascl1 protein, mouse; C102938:Neurog2 protein, mouse; C486223:Yap1 protein, mouse