Brain, eye, and face defects as a result of ectopic localization of Sonic hedgehog protein in the developing rostral neural tube.
BACKGROUND
Normal development of the face, eyes, and brain requires the coordinated expression of many genes. One gene that has been implicated in the development of each of these structures encodes the secreted protein, Sonic hedgehog (Shh). During central nervous system development, Shh is required for ventral specification along the entire neural axis. To further explore the role of Shh in chick brain and craniofacial development, we overexpressed Shh in the developing rostral neural tube


METHODS
In order to determine if Shh is sufficient to ventralize the forebrain, we localized ectopically recombinant Shh protein to the rostral neural tube of chick embryos. The resulting embryos were evaluated morphologically and by assaying gene expression.


RESULTS
Disruption in normal gene expression patterns was observed with a reduction or loss in expression of genes normally expressed in the dorsal forebrain (wnt-3a, wnt-4, and Pax-6) and expansion of ventrally expressed genes dorsally (HNF-3beta, Ptc). In addition to the genetic alterations observed in the neural tube, a craniofacial phenotype characterized by a reduction in many cranial neural crest-derived structures was observed. The eyes of Shh-treated embryos were also malformed. They were small with expansion of the retinal pigmented epithelium, enlarged optic stalks, and a reduction of neural retina.


CONCLUSIONS
The ectopic localization of recombinant Shh protein in the rostral neural tube resulted in severe craniofacial anomalies and alterations of gene expression predicted by other studies. The system employed appears to be a model for studying the embryogenesis of malformations that involve the brain, eyes, and face.
Nasrallah
I
I
Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Golden
J A
JA
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000235:genetics; D000015:Abnormalities, Multiple / Q000139:chemically induced* / Q000235:genetics; D000818:Animals; D001921:Brain / Q000002:abnormalities*; D002478:Cells, Cultured; D002642:Chick Embryo; D004627:Embryonic Induction; D005124:Eye Abnormalities / Q000139:chemically induced* / Q000235:genetics; D005145:Face / Q000002:abnormalities*; D053823:Hedgehog Proteins; D017403:In Situ Hybridization; D009420:Nervous System / Q000187:drug effects / Q000196:embryology*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000633:toxicity*
D053823:Hedgehog Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators