7 February, 2001. 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
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.
Reference:Sun Yi, Nadal-Vicens Mireya, Misono Stephanie, Lin Michael, Zubiaga Ana, Hua Xianxing, Fan Guoping, Greenberg Michael. Neurogenin
promotes neurogenesis and inhibits glial differentiation by independent
mechanisms. Cell 2001 Feb 8. Abstract