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The Journal of Neuroscience, March 22, 2006, 26(12):3102-3108; doi:10.1523/JNEUROSCI.4829-05.2006

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Cellular/Molecular
Notch1 Signaling Regulates Radial Glia Differentiation through Multiple Transcriptional Mechanisms

Brooke A. Patten,¹ S. Pablo Sardi,¹ Samir Koirala,¹ Masato Nakafuku,² and Gabriel Corfas¹

¹Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and ²Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039

Correspondence should be addressed to Dr. Gabriel Corfas, Division of Neuroscience, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. Email: gabriel.corfas{at}tch.harvard.edu

Signaling by the Notch1 receptor is critical for the formation of radial glia in the developing nervous system. We have shown previously that Notch1 regulates the molecular and morphological differentiation of radial glia through the transcriptional activation of at least two genes, brain lipid binding protein (BLBP) and the erbB2 receptor tyrosine kinase. However, the mechanisms by which this occurs remained undefined. Here we demonstrate that Notch1 effects on radial glia gene expression are mediated by two downstream mechanisms, one that the depends on Suppressor of Hairless [Su(H)] and the other on Deltex1 (DTX1). These two Notch1-binding proteins contribute to the regulation of BLBP and erbB2 expression, respectively. Importantly, our results suggest that, although these events can occur simultaneously, a hierarchical relationship might exist between DTX1 and Su(H), because overexpression of DTX1 or a dominant-negative form of this protein inhibits Su(H)-mediated events but not vice versa. In contrast to the effects of DTX1 overexpression, interference RNA-mediated knock-down of DTX1 blocks Notch1-induced erbB2 promoter activation and radial glia formation selectively, without affecting Su(H)-dependent pathways, indicating that loss of DTX1 expression and expression of dominant-negative DTX1 result in different alterations in cell differentiation and gene expression. Together, these results show that Notch1 regulates radial glia formation through two distinct transcriptional mechanisms and that the outcomes of Notch1 signaling may depend on the relative expression levels of its coregulators.

Key words: Notch1; Su(H); erbB; cerebellum; glia; BLBP; DTX

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Received Nov. 9, 2005; revised Jan. 10, 2005; accepted Feb. 3, 2006.

Correspondence should be addressed to Dr. Gabriel Corfas, Division of Neuroscience, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. Email: gabriel.corfas{at}tch.harvard.edu

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