A Binding Site for Homeodomain and Pax Proteins Is Necessary for L1 Cell Adhesion Molecule Gene Expression by Pax-6 and Bone Morphogenetic Proteins

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 5; pp. 2420 - 2425
• Main Authors: Meech, Robyn, Kallunki, Pekka, Edelman, Gerald M., Jones, Frederick S.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 02.03.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Base Sequence; beta-Galactosidase - genetics; Binding Sites; Biological Sciences; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins - metabolism; Bones; Brain - metabolism; Calcium-Binding Proteins - genetics; Cell Line; Cells; Consensus Sequence; COS Cells; DNA-Binding Proteins - metabolism; Embryos; Exons; Eye Proteins; Gene expression; Gene expression regulation; Genes; Genes, Reporter; Homeodomain Proteins - metabolism; Introns; Leukocyte L1 Antigen Complex; Membrane Glycoproteins - genetics; Mesencephalon; Mesencephalon - metabolism; Mice; Mice, Transgenic; Molecules; Neural Cell Adhesion Molecules - genetics; Neurology; Neurons; Neurons - metabolism; Oligodeoxyribonucleotides - chemistry; Oligodeoxyribonucleotides - metabolism; Paired Box Transcription Factors; PAX3 Transcription Factor; PAX6 Transcription Factor; Proteins; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - metabolism; Repressor Proteins; Sequence Deletion; Telencephalon; Telencephalon - metabolism; Transcription Factors - metabolism; Transfection; Transforming Growth Factor beta; Transgenes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.5.2420

The cell adhesion molecule L1 regulates axonal guidance and fasciculation during development. We previously identified the regulatory region of the L1 gene and showed that it was sufficient for establishing the neural pattern of L1 expression in transgenic mice. In the present study, we characterize a DNA element within this region called the HPD that contains binding motifs for both homeodomain and Pax proteins and responds to signals from bone morphogenetic proteins (BMPs). An ATTA sequence within the core of the HPD was required for binding to the homeodomain protein Barx2 while a separate paired domain recognition motif was necessary for binding to Pax-6. In cellular transfection experiments, L1-luciferase reporter constructs containing the HPD were activated an average of 4-fold by Pax-6 in N2A cells and 5-fold by BMP-2 and BMP-4 in Ng108 cells. Both of these responses were eliminated on deletion of the HPD from L1 constructs. In transgenic mice, deletion of the HPD from an L1-lacZ reporter resulted in a loss of β -galactosidase expression in the telencephalon and mesencephalon. Collectively, our experiments indicate that the HPD regulates L1 expression in neural tissues via homeodomain and Pax proteins and is likely to be a target of BMP signaling during development.