A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers

Yongsu Jeong; Kenia El-Jaick; Erich Roessler; Maximilian Muenke; Douglas J. Epstein

doi:10.1242/dev.02239

journal article Open Access Feb 15, 2006

A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers

Yongsu Jeong Kenia El-Jaick Erich Roessler Maximilian Muenke Douglas J. Epstein

Development Vol. 133 No. 4 pp. 761-772 · The Company of Biologists

View at Publisher Save 10.1242/dev.02239

Abstract

The secreted protein sonic hedgehog (Shh) plays an integral role in forming the ventral midline of the vertebrate central nervous system (CNS). In the absence of Shh function, ventral midline development is perturbed resulting in holoprosencephaly (HPE), a structural malformation of the brain, as well as in neuronal patterning and path finding defects along the length of the anteroposterior neuraxis. Central to the understanding of ventral neural tube development is how Shh transcription is regulated in the CNS. To address this issue, we devised an enhancer trap assay to systematically screen 1 Mb of DNA surrounding the Shh locus for the ability to target reporter gene expression to sites of Shh transcription in transgenic mouse embryos. This analysis uncovered six enhancers distributed over 400 kb,the combined activity of which covered all sites of Shh expression in the mouse embryonic CNS from the ventral forebrain to the posterior extent of the spinal cord. To evaluate the relative contribution of these enhancers to the overall pattern of Shh expression, individual elements were deleted in the context of a transgenic Bac reporter assay. Redundant mechanisms were found to control Shh-like reporter activity in the ventral spinal cord, hindbrain and regions of the telencephalon, whereas unique elements regulated Shh-like expression in the ventral midbrain, the majority of the ventral diencephalon and parts of the telencephalon. Three ventral forebrain enhancers locate on the distal side of translocation breakpoints that occurred upstream of Shh in human cases of HPE, suggesting that displacement of these regulatory elements from the Shh promoter is a likely cause of HPE in these individuals.

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Details

Published: Feb 15, 2006
Vol/Issue: 133(4)
Pages: 761-772

Authors

Y

Yongsu Jeong

Department of Genetics, University of Pennsylvania School of Medicine,Clinical Research Building, Room 470, 415 Curie Boulevard, Philadelphia, PA 19104, USA.

K

Kenia El-Jaick

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-3717, USA.

E

Erich Roessler

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-3717, USA.

M

Maximilian Muenke

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-3717, USA.

D

Douglas J. Epstein

Department of Genetics, University of Pennsylvania School of Medicine,Clinical Research Building, Room 470, 415 Curie Boulevard, Philadelphia, PA 19104, USA.

Cite This Article

Yongsu Jeong, Kenia El-Jaick, Erich Roessler, et al. (2006). A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers. Development, 133(4), 761-772. https://doi.org/10.1242/dev.02239

A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers

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