Ascl1 and Neurog2 form novel complexes and regulate Delta-like3 (Dll3) expression in the neural tube

• Published in: Developmental biology Vol. 328; no. 2; pp. 529 - 540
• Main Authors: Henke, R. Michael, Meredith, David M., Borromeo, Mark D., Savage, Trisha K., Johnson, Jane E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-04-2009
• Subjects: Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - physiology; bHLH transcription factors; Binding Sites; Delta; Dimerization; Dorsal spinal cord development; E-Box Elements; Gene Expression Regulation, Developmental; Gene regulation; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - physiology; Mash1; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Mice, Transgenic; Molecular Sequence Data; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neural Tube - embryology; Neural Tube - physiology; Neurogenin; Neurons - physiology; Notch ligands; Promoter Regions, Genetic; Stem Cells - physiology; Mash1; bHLH transcription factors; Delta; Gene regulation; Notch ligands; Dorsal spinal cord development; Neurogenin
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2009.01.007

Delta-like 3 (Dll3) is a Delta family member expressed broadly in the developing nervous system as neural progenitor cells initiate differentiation. A proximal promoter sequence for Dll3 is conserved across multiple species and is sufficient to direct GFP expression in a Dll3-like pattern in the neural tube of transgenic mice. This promoter contains multiple E-boxes, the consensus binding site for bHLH factors. Dll3 expression and the activity of the Dll3-promoter in the dorsal neural tube depends on the basic helix–loop–helix (bHLH) transcription factors Ascl1 (Mash1) and Neurog2 (Ngn2). Mutations in each E-box identified in the Dll3-promoter allowed distinct enhancer or repressor properties to be assigned to each site individually or in combination. In addition, each E-box has distinct characteristics relative to binding of bHLH factors Ascl1, Neurog1, and Neurog2. Surprisingly, novel Ascl1 containing DNA binding complexes are identified that interact with specific E-box sites within the Dll3-promoter in vitro. These complexes include Ascl1/Ascl1 homodimers and Ascl1/Neurog2 heterodimers, complexes that in some cases require additional undefined factors for efficient DNA binding. Thus, a complex interplay of E-box binding proteins spatially and temporally regulate Dll3 levels during neural tube development.