The RNA-binding protein Musashi-1 regulates neural development through the translational repression of p21WAF-1.
RNA-binding proteins regulate cell fate decisions during nervous system development. The Msi family of RNA-binding proteins is expressed in multipotential neural progenitors, and is required for maintaining cells in a proliferative state. We demonstrate that Msi-1's ability to regulate progenitor maintenance is through the translational inhibition of the cyclin-dependent kinase inhibitor p21WAF-1. Msi-1 ectopic expression increases the proliferation rate and the capacity to regulate p21WAF-1 protein expression, independent of p53. The 3' untranslated region (UTR) of the native p21(WAF-1) mRNA contains a Msi-1 consensus-binding site that permits Msi-1 to directly repress the translation of p21WAF-1 protein. Reduction of Msi-1 through antisense leads to aberrant p21WAF-1 expression, which significantly impairs neural differentiation. A double knockdown for p21WAF-1 and Msi-1 rescues the production of mature MAP+ neurons. Our results further elucidate the symbiotic relationship between cell cycle withdrawal and the onset of differentiation in the developing nervous system, as well as increasing the understanding of the influence that RNA-binding proteins serve in regulating these processes.
Battelli
Chiara
C
The Center for Regenerative Medicine, Maine Medical Center Research Institute, 81 Research Drive Scarborough, ME 04074, USA.
Nikopoulos
George N
GN
Mitchell
Jane G
JG
Verdi
Joseph M
JM
D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C491297:MSI1 protein, human; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D018844:Cyclin-Dependent Kinases