Stem cell researchers know only too well that most adult neural precursor cells differentiate into astrocytes, not the coveted nerve cells. Even when stimulated by the addition of neuron-inducing growth factors, such as PDGF or NT-3, only a small percentage of cultured stem cells generally mature into neurons. A report in tomorrow's Cell helps explain the biology behind this problem.
Michael Greenberg of Harvard Medical School, with colleagues there and elsewhere, reports that the transcription factor neurogenin does double duty in nudging progenitor cells down a neuronal lineage. It blocks the phosphorylation of STAT3, a signal transducer and transcriptional activator required for astrocyte differentiation. It also sequesters CBP/p300-a transcriptional coactivator known to bind to the promotors of many different genes-away from astrocyte genes, such as the one for glial fibrillary acidic protein and others. Instead, neurogenin directs CBP/p300 complexed with the protein smad1 toward the expression of the early neuronal marker neuroD.
This protein-protein interaction represents a new mechanism by which a transcriptional activator can influence which genes are read. Previously, scientists thought this class of proteins acted mostly through their DNA-binding sites.
The finding helps explain why, in the developing cortex, pluripotent neural precursors first give rise to neurons before generating astrocytes and, finally, oligodendrocytes. These waves coincide with neurogenin expression levels, suggesting that high neurogenin initially keeps a lid on alternative fates, while low neurogenin in cells generated perinatally allows glial differentiation to proceed. The study advances researchers' understanding of how different protein complexes cooperate inside a cell to determine its fate. Previous work has focused on growth factors that affect cell fate decisions from the outside.
When added to adult stem cells grown in culture, neurogenin effects neurogenesis even in the presence of glial-inducing cues, such as CNTF, Greenberg says. He is now working to understand the regulation of neurogenin expression, hoping that the ability to manipulate neurogenin transcription will help efforts at developing therapeutic stem cells to replace injured or degenerated nerve cells.—Gabrielle Strobel
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- Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G, Greenberg ME. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell. 2001 Feb 9;104(3):365-76. PubMed.