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doi: 10.1242/10.1242/dev.00539
,
1 Institut de Génétique et de Biologie Moléculaire et
Cellulaire, BP 163, 67404 Illkirch, Cedex, CU de Strasbourg, France
2 Max Planck Institute of Biophysical Chemistry, Department of Molecular Cell
Biology, Am Fassberg 11, D-37077 Göttingen, Germany
* Present address: Institute of Cell Biology and Tissue Engineering, Via di
Castel Romano 100/102, 00128 Rome, Italy
Present address: Division of Molecular Neurobiology, National Institute for
Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
Author for correspondence (e-mail:
fguille{at}nimr.mrc.ac.uk)
Accepted 9 April 2003
Expression of the proneural gene Neurogenin2 is controlled by several enhancer elements, with the E1 element active in restricted progenitor domains in the embryonic spinal cord and telencephalon that express the homeodomain protein Pax6. We show that Pax6 function is both required and sufficient to activate this enhancer, and we identify one evolutionary conserved sequence in the E1 element with high similarity to a consensus Pax6 binding site. This conserved sequence binds Pax6 protein with low affinity both in vitro and in vivo, and its disruption results in a severe decrease in E1 activity in the spinal cord and in its abolition in the cerebral cortex. The regulation of Neurogenin2 by Pax6 is thus direct.
Pax6 is expressed in concentration gradients in both spinal cord and telencephalon. We demonstrate that the E1 element is only activated by high concentrations of Pax6 protein, and that this requirement explains the restriction of E1 enhancer activity to domains of high Pax6 expression levels in the medioventral spinal cord and lateral cortex. By modifying the E1 enhancer sequence, we also show that the spatial pattern of enhancer activity is determined by the affinity of its binding site for Pax6. Together, these data demonstrate that direct transcriptional regulation accounts for the coordination between mechanisms of patterning and neurogenesis. They also provide evidence that Pax6 expression gradients are involved in establishing borders of gene expression domains in different regions of the nervous system.
Key words: Spinal cord, Cerebral cortex, Transcriptional enhancer, Chick, Electroporation
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