The SWI/SNF chromatin remodeling protein Brg1 is required for vertebrate neurogenesis and mediates transactivation of Ngn and NeuroD
2004
Chromatin remodeling complexes play crucial roles in transcription and are
implicated in processes including cell proliferation, differentiation and
embryonic patterning. Brg1 is the catalytic subunit of the SWI/SNF chromatin
remodeling complex and shows neural-enriched expression. Although early
lethality of Brg1 -null mice reflects its importance in embryogenesis,
this phenotype precluded further study of specific Brg1-dependent
developmental processes. Here, we have identified a requirement of Brg1 for
both Xenopus primary neurogenesis and neuronal differentiation of
mammalian P19 embryonic carcinoma cells. In Xenopus , loss of Brg1
function did not affect neural induction or neural cell fate determination.
However, the Sox2 -positive, proliferating neural progenitor cell
population was expanded, and expression of a terminally differentiated
neuronal marker, N-tubulin , was diminished upon loss of Brg1
activity, suggesting that Brg1 is required for neuronal differentiation. The
ability of the bHLH transcription factors Ngnr1 and NeuroD to drive neuronal
differentiation was also abolished by loss of Brg1 function, indicating that
Brg1 is essential for the proneural activities of Ngnr1 and NeuroD. Consistent
with this, dominant-negative interference with Brg1 function in P19 cells
suppressed neuronal differentiation promoted by NeuroD2, showing the
requirement of Brg1 for neuronal differentiation is conserved in mammalian
cells. Finally, we discovered that Brg1 physically associates with both Ngnr1
and NeuroD and that interference with Brg1 function blocks Neurogenin3- and
NeuroD2-mediated reporter gene transactivation. Together, our results
demonstrate that Brg1 (and by inference the SWI/SNF complex) is required for
neuronal differentiation by mediating the transcriptional activities of
proneural bHLH proteins.
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